Polyhydroxyphenol derivatives and preventive and therapeutic agents for bone and cartilage diseases containing the same

ABSTRACT

Compounds useful as preventive and therapeutic agents for bone and cartilage diseases; and drug compositions containing the same. The compounds are polyhydroxyphenol derivatives of general formula (I)                    
     and quinione analogues derived therefrom (wherein R 1  is alkyl, optionally substituted benzyl or optionally substituted aryl; R 2  is hydrogen, alkyl, alkenyl or optionally substituted benzyl; R 3  is hydrogen, alkyl, alkenyl, optionally substituted benzyl, hydroxyl, alkoxy, alkenyloxy or optionally substituted benzyloxy; R 4  is hydrogen, alkyl, alkenyl, optionally substituted benzyl or hydroxyl; and R 5  and R 6  are each independently hydrogen, alkyl, alkenyl or optionally substituted benzyl). The polyhydroxyphenol derivatives and the quinone analogues exhibit a potent inhibitory activity against bone resorption and are useful as preventive and therapeutic agents for bone and cartilage diseases.

This is the U.S. National Stage Application of PCT/JP97/01625 filed May14, 1997.

TECHNICAL FIELD

This invention relates to novel polyhydroxyphenol derivatives, saltsthereof, and medicinal compositions containing the same which have beendeveloped for the purpose of being used for preventive and therapeuticosteolytic diseases such as, for example, malignant hypercalcemia,Paget's disease, and osteoporosis and diseases accompanying chondraldegeneration and necrosis such as, for example, osteoarthritis apt toattack knees, shoulders, and hip joints, femoral head necrosis, andrheumatoid arthritis.

BACKGROUND ART

Japan has been plunging into such an aging society as has never existedto date and has come to encounter the spread of such osteolytic diseasesas osteoporosity as a serious social issue. The term “osteolyticdisease” means diseases of bones induced by abnormal aggravation ofosteolysis such as, for example, malignant hypercalcemia causes bymyeloma and lymphoma, Paget's disease caused by local osteolysis, andosteoporosis caused by various factors like aging and menopause. Thegrowth in the number of aged persons laid up in bed on account of bonefractures which originate in such osteolytic diseases ultimately resultsin a huge addition to the national medical expenses. At present, vitaminD preparation, calcitonin preparation, and ipriflavone preparation arebeing used for the therapy of these diseases. The treatment with thesemedicines allows no radical cure but barely serves as a symptomaticmeasure. The osteoarthritis, femoral head necrosis, and rheumatoidarthritis form a group of diseases which occur when the articularcartilage and cartilaginified bone are aggravated until degeneration andnecrosis by various factors such as, for example, mechanical stress,aging, and inflammation and ultimately suffered to induce defects ofbones and cartilages. These chondral defects, by deforming joints andcausing pains therein, have a conspicuous effect in the degradation ofthe quality of daily life of the affected persons. Though the diseasesof this category are being treated with hyaluronic acid,anti-inflammatory agent, and analgesic agent, a medicine which iscapable of effectively inhibiting or curing chondral defects has not yetbeen developed.

The object of this invention, therefore, is to improve the existingmethod of therapy and to provide a novel and more effective preventiveand therapeutic medicine.

The present inventors formerly discovered that a substance exhibiting apowerful activity to repress osteolysis is contained in the hops andthat the active principle of this substance is an α acid and an iso αacid represented by the following general formula (XIII)(JP-A-07-330594).

(wherein R₁ represents 2-methylpropyl group, 2-propyl group, or 2-butylgroup).

It has been pointed out, however, that since the substance (XIII)effective in actively repressing the osteolysis mentioned above is anatural product, it tends to entail such problems as the dependency ofthe harvest of hops on weather conditions and the difficulty incurred inthe procurement thereof. The inventors, with the expectation that thecompounds approximating closely to this substance have the possibilityof affording active substances as powerful as the aforementionedsubstance (XIII) capable of repressing osteolysis, have tried structuralalterations of the active substance (XIII) mentioned above, synthesizedmany compounds, and tested them for activity. As a result, they havediscovered powerful activity in the polyhydroxyphenol derivativesrepresented by the general formulas (I)-(XII) to be described hereinbelow. The present invention has been perfected based 0n this discovery.

DISCLOSURE OF THE INVENTION

This invention relates to a compound represented by the followinggeneral formula (I)

(wherein R₁ represents a branched or straight-chain alkyl group of 1-15carbon atoms, a substituted or unsubstituted benzyl group, or asubstituted or unsubstituted aryl group; R₂ represents a hydrogen atom,a branched or straight-chain alkyl group of 1-15 carbon atoms, abranched or straight-chain alkenyl group of 2-15 carbon atoms, or asubstituted or unsubstituted benzyl group; R₃ represents a hydrogenatom, a branched or straight-chain alkyl group of 1-15 carbon atoms, abranched or straight-chain alkenyl group of 2-15 carbon atoms, asubstituted or unsubstituted benzyl group, a hydroxyl group, a branchedor straight-chain alkoxy group of 1-15 carbon atoms, a branched orstraight-chain alkenyloxy group of 2-15 carbon atoms, or a substitutedor unsubstituted benzyloxy group; R₄ represents a hydrogen atom, abranched or straight-chain alkyl group of 1-15 carbon atoms, a branchedor straight-chain alkenyl group of 2-15 carbon atoms, a substituted orunsubstituted benzyl group, or a hydroxyl group; and R₅ and R₆independently represent a hydrogen atom, a branched or straight-chainalkyl group of 1-15 carbon atoms, a branched or straight-chain alkenylgroup of 2-15 carbon atoms, or a substituted or unsubstituted benzylgroup; providing that the case in which R₂ and R₃ are each a hydrogenatom or a 3-methyl-2-butenyl group when R₄ is a hydroxyl group, R₃ andR₆ are each a hydrogen atom, and R₁ is a 2-propyl group or 2-butyl groupand the case in which R₂ and R₃ are each a hydrogen atom, a3-methyl-2-butenyl group, or a 3-methyl-n-butyl group when R₄ is ahydroxyl group, R₅ and R₆ are each a hydrogen atom, and R₁ is a2-methylpropyl group are excluded) or an acylfluoroglucinol derivativethereof which is a salt thereof.

More specifically, this invention relates to a compound represented bythe following general formula (II)

(wherein R₁ represents a 2-methylpropyl group or a 2,6-dimethylheptylgroup; and R₂ and R₃ independently represent a hydrogen atom, a3-methyl-2-butenyl group, a 3,7-dimethyl-2,6-octadienyl group, or asubstituted or unsubstituted benzyl group; providing that the case inwhich R₁ is a 2-methylpropyl group and R₂ and R₃ independently are ahydrogen atom or a 3-methyl-2-butenyl group is excluded)

or an acylfluoroglucinol derivative thereof which is a salt thereof anda compound represented by the following general formula (III)

 (wherein R₁ represents a branched or straight-chain alkyl group of 1-15carbon atoms, a substituted or unsubstituted benzyl group, or asubstituted or unsubstituted aryl group; R₂ and R₄ independentlyrepresent a hydrogen atom, a branched or straight-chain alkyl group oralkenyl group of 1-15 carbon atoms, or a substituted or unsubstitutedbenzyl group; and R₅, R₆, and R₇ independently represent a hydrogenatom, a branched or straight-chain alkyl group or alkenyl group of 1-15carbon atoms, or a substituted or unsubstituted benzyl group) or anacylhydroxyhydroquinone derivative thereof which is a salt thereof.

This invention further relates to a compound represented by thefollowing general formula (IV)

(wherein R₁ represents a branched or straight-chain alkyl group of 1-15carbon atoms, a substituted or unsubstituted benzyl group, or asubstituted or unsubstituted aryl group; R₂ represents a hydrogen atom,a branched or straight-chain alkyl group of 1-15 carbon atoms, abranched or straight-chain alkenyl group of 2-15 carbon atoms, or asubstituted or unsubstituted benzyl group; R₃ represents a branched orstraight-chain alkyl group of 1-15 carbon atoms, a branched orstraight-chain alkenyl group of 2-15 carbon atoms, or a substituted orunsubstituted benzyl group; and R₈ represents a hydroxyl group, abranched or straight-chain alkyl group of 1-15 carbon atoms, a branchedor straight-chain alkenyl group of 2-15 carbon atoms, or a substitutedor unsubstituted benzyl group; providing that the case in which R₂ andR₃ are each a 3-methyl-2-butenyl group when R₁ is a methyl group and R₈is a hydroxyl group and the case in which at least two or three membersof the class consisting of R₂, R₃, and R₈ are each a 3-methyl-2-butenylgroup and the remaining member is a hydrogen atom or a hydroxyl groupwhen R₁ is a 2-propyl group or 2-methylpropyl group are excluded) or anacyldihydroxycyclohexadienone derivative thereof which is a saltthereof.

More specifically, this invention relates to a compound represented bythe following general formula (V)

(wherein R₁ represents a 2-methylpropyl group or a 2,6-dimethylheptylgroup; R₂ represents a hydrogen atom, a 3-methyl-2-butenyl group, a3,7-dimethyl-2,6-octadienyl group, or a substituted or unsubstitutedbenzyl group; and R₃ represents a 3-methyl-2-butenyl group, a3,7-dimethyl-2,6-octadienyl group, or a substituted or unsubstitutedbenzyl group; providing that the case in which R₁ is a 2-methylpropylgroup or a 2-propyl group, R₂ is a hydrogen atom or a 3-methyl-2-butenylgroup, and R₃ is a 3-methyl-2-butenyl group is excluded) or an

acyldihydroxycyclohexadienone derivative thereof which is a salt thereofand a compound represented by the following general formula (VI)

 (wherein R₁ represents a 2-methylpropyl group or a substituted orunsubstituted aryl group; and R₂ and R₃ each represent a3-methyl-2-butenyl group, or a substituted or unsubstituted benzylgroup; providing that the case in which R₁ is a 2-methylpropyl group andR₂ and R₃ are each a 3-methyl-2-butenyl group is excluded) or an

acyltrihydroxycyclohexadienone derivative thereof which is a saltthereof.

Further, this invention relates to a medicinal composition composed of acompound represented by the general formula (VII).

(wherein R₁ represents a branched or straight-chain alkyl group of 1-15carbon atoms, a substituted or unsubstituted benzyl group, or asubstituted or unsubstituted aryl group; R₂ represents a hydrogen atom,a branched or straight-chain alkyl group of 1-15 carbon atoms, abranched or straight-chain alkenyl group of 2-15 carbon atoms, or asubstituted or unsubstituted benzyl group; R₃ represents a hydrogenatom, a branched or straight-chain alkyl group of 1-15 carbon atoms, abranched or straight-chain alkenyl group of 2-15 carbon atoms, asubstituted or unsubstituted benzyl group, a hydroxyl group, a branchedor straight-chain alkoxy group of 1-15 carbon atoms, a branched orstraight-chain alkenyloxy group of 2-15 carbon atoms, or a substitutedor unsubstituted benzyloxy group; R₄ represents a hydrogen atom, abranched or straight-chain alkyl group of 1-15 carbon atoms, a branchedor straight-chain alkenyl group of 2-15 carbon atoms, a branched orstraight-chain benzyl group, or a hydroxyl group; and R₅ and R₆ eachindependently represent a hydrogen atom, a branched or straight-chainalkyl group of 1-15 carbon atoms, a branched or straight-chain alkenylgroup of 2-15 carbon atoms, or a substituted or unsubstituted benzylgroup) or one or more pharmaceutically acceptable salts thereof and apharmaceutically acceptable carrier therewith.

Specifically, this invention relates to a medicinal compositioncontaining an acylfluoroglucinol derivative which is a compoundrepresented by the following general formula (VIII)

(wherein R₁ represents a 2-methylpropyl group or a 2,6-dimethylheptylgroup; and R₂ and R₃ each independently represent a hydrogen atom, a3-methyl-2-butenyl group, a 3,7-dimethyl-2,6-octadienyl group, or asubstituted or unsubstituted benzyl group) or a pharmaceuticallyacceptable salt thereof and an acylhydroxyhydroquinone derivative whichis a compound represented by the following general formula (IX)

(wherein R₁ represents a branched or straight-chain alkyl group of 1-15carbon atoms, a substituted or unsubstituted benzyl group, or asubstituted or unsubstituted aryl group; R₂ and R₄ each independentlyrepresent a hydrogen atom, a branched or straight-chain alkyl group oralkenyl group of 1-15 carbon atoms, or a substituted or unsubstitutedbenzyl group; and R₅, R₆, and R₇ each independently represent a hydrogenatom, a branched or straight-chain alkyl group or alkenyl group of 1-15carbon atoms, or a substituted or unsubstituted benzyl group) or one ormore pharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable carrier therewith.

This invention further relates to a medicinal composition containing anacyldihydroxycyclohexadienone derivative which is a compound representedby the following general formula (X)

(wherein R₁ represents a branched or straight-chain alkyl group of 1-15carbon atoms, a substituted or unsubstituted benzyl group, or asubstituted or unsubstituted aryl group; R₂ represents a hydrogen atom,a branched or straight-chain alkyl group of 1-15 carbon atoms, abranched or straight-chain alkenyl group of 2-15 carbon atoms, or asubstituted or unsubstituted benzyl group; R₃ represents a branched orstraight-chain alkyl group of 1-15 carbon atoms, a branched orstraight-chain alkenyl group of 2-15 carbon atoms, or a substituted orunsubstituted benzyl group; and R₈ represents a hydroxyl group, abranched or straight-chain alkyl group of 1-15 carbon atoms, a branchedor straight-chain alkenyl group of 2-15 carbon atoms, or a substitutedor unsubstituted benzyl group) or one or more pharmaceuticallyacceptable salts thereof and a pharmaceutically acceptable carriertherewith.

More specifically, this invention relates to a medicinal compositioncontaining an acyldihydroxycyclohexadienone derivative which is acompound represented by the following general formula (XI)

(wherein R₁ represents a 2-methylpropyl group or a 2,6-dimethylheptylgroup; R₂ represents a 3-methyl-2-butenyl group, a3,7-dimethyl-2,6-octadienyl group, or a substituted or unsubstitutedbenzyl group; and R₃ represents a 3-methyl-2-butenyl group, a3,7-dimethyl-2,6-octadienyl group, or a substituted or unsubstitutedbenzyl group) or a pharmaceutically acceptable salt thereof and anacyltrihydroxycyclohexadienone derivative which is a compoundrepresented by the following general formula (XII)

(wherein R₁ represents a 2-methylpropyl group or a substituted orunsubstituted aryl group; and R₂ and R₃ each represent a3-methyl-2-butenyl group, or a substituted or unsubstituted benzylgroup) or one or more pharmaceutically acceptable salts thereof and apharmaceutically acceptable carrier therewith.

Further, this invention relates to a preventive and therapeutic methodfor a disease affecting bone and cartilage, which method comprisesadministering to the patient of the disease one or more members selectedfrom the group consisting of the compounds represented by the generalformulas (I), (IV), (IIV), and (X) in an amount effective in preventingor curing the disease. It further relates to the use of one or moremembers selected from the group consisting of the compounds representedby the general formulas (I), (IV), (IIV), and (X) for the production ofa medicinal composition intended for the prevention or therapy of adisease affecting bone and cartilage.

The medicinal composition of the present invention possesses an activityto inhibit osteolysis and, therefore, is useful as a preventive andtherapeutic agent for the diseases affecting bone and cartilage.

MODE OF EMBODIMENT OF THE INVENTION

The alkyl group in the compound of this invention is a branched orstraight-chain alkyl group of 1-15 carbon atoms, preferably 1-10 carbonatoms. A methyl group, an n-propyl group, an isopropyl group, an n-butylgroup, a sec-butyl group, an isobutyl group, varying pentyl groups,varying hexyl groups, and varying heptyl groups may be cited as concreteexamples of the alkyl group. As the alkyl groups denoted by thesubstituent, R₁, 2-propyl group, 2-methylpropyl group,2,6-dimethylheptyl group, and 2,6,10-trimethylundecanyl group arepreferred concrete examples.

The alkenyl group in the compound is a branched or straight-chainalkenyl group of 2-15 carbon atoms, preferably 2-10 carbon atoms,possessing one or more unsaturated carbon-carbon bonds. A vinyl group,an allyl group, a butenyl group, a pentenyl group, and an octadienylgroup may be cited as concrete examples of the alkenyl group.Preferably, 3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group,and 3,7,11-trimethyl-2,6,10-dodecatrienyl group may be cited as otherexamples.

As concrete examples of the aryl group in the compound, heterocyclicaromatic substituents such as a pyridine ring, a pyrimidine ring, apyrrole ring, an imidazole ring, and a thiophene ring may be citedbesides the groups possessing a six-member aromatic ring. Preferably, aphenyl group, a naphthyl group, etc. may be cited. Particularlypreferably, a phenyl group may be cited.

The aryl group and the benzyl group may be substituted with a varyingsubstituent so long as the substitution may not impair the physiologicalactivity of the compound of this invention. As concrete examples of thesubstituent, halogen atoms such as chlorine, fluorine, and bromine, ahydroxyl group, alkoxy groups of 1-15 carbon atoms, alkenyloxy groups of2-15 carbon atoms, and acyl groups such as acetyl group and propionylgroup may be cited.

As preferred concrete examples of the compound represented by thegeneral formula (I) according to this invention,

(2,4,6-Trihydroxyphenyl) (2,6-dimethylheptyl) ketone (Compound No. 6),

{3-(3-Methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (2,6-dimethylheptyl)ketone (Compound No. 23),

{3,5-Bisbenzyl-2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (CompoundNo. 34),

{3,5-Bis(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl)}(2-methylpropyl) ketone (Compound No. 19),

{(3-(3-Methyl-2-butenyl)-2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone(Compound No. 26),

{3,6-Bis(3-methyl-2-butenyl)-2,4,5-trihydroxyphenyl} (2-methylpropyl)ketone (Compound No. 25),

{(6-(3-Methyl-2-butenyl)-2,4,5-trihydroxyphenyl} (2-methylpropyl)ketonemono(3-methyl-2-butenyl) ether (Compound No. 27),

(2,4,5-Trihydroxyphenyl) (2-methylpropyl) ketonemono(3-methyl-2-butenyl)ether (Compound No. 28),

{3,5-Bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl)} (phenylmethyl)ketone (Compound No. 39),

{3-(3-Methyl-2-butenyl)-2,4,6-trihydroxyphenyl)} (phenylmethyl) ketone(Compound No. 42),

{3,5-Bis(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl)}(phenylmethyl) ketone (Compound No. 43),

{3-(3,7-Dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl)} (phenylmethyl)ketone (Compound No. 46),

{2-Hydroxy-6-methyl-4-(3-methyl-2-butenyloxy)phenyl} (2-methylpropyl)ketone (Compound No. 48),

{2,4-Dihydroxy-6-methyl-3-(3-methyl-2-butenyl) phenyl} (2-methylpropyl)ketone (Compound No. 49),

{4,6-Dihydroxy-2-methyl-3-(3-methyl-2-butenyl)phenyl} (3-methylpropyl)ketone (Compound No. 50),

{3,5-Bis(3-methyl-2-butenyl)-2-hydroxy-6-methyl-4-(3-methyl-2-butenyloxy)phenyl)}(2-methylpropyl) ketone (Compound No. 51),

{2-Hydroxy-4-(3-methyl-2-butenyloxy)phenyl} (2-methylpropyl) ketone(Compound No. 53),

{2,4-Dihydroxy-3-(3-methyl-2-butenyl)phenyl} (2-methylpropyl) ketone(Compound No. 54), and

{2,4-Dihydroxy-5-(3-methyl-2-butenyl)phenyl} (2-methylpropyl) ketone(Compound No. 55) may be cited.

As concrete examples of the compound represented by the general formula(IV) of this invention,

2,2-bis(3,7-dimethyl-2,6-octadienyl)-3,5-dihydroxy-6-(3-methyl-1-oxobutyl)cyclohexa-3,5-dienone(Compound No. 21),

3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-2,2,4-tris(3,7-dimethyl-2,6-octadienyl)cyclohexa-3,5-dienone(Compound No. 20),

2,2-bisbenzyl-3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-cyclohexa-3,5-dienone(Compound No. 35),

3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-2,2,4-trisbenzylcyclohexa-3,5-dienone(Compound No. 36),

2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(3,7-dimethyl-1-oxooctyl)cyclohexa-3,5-dienone(Compound No. 24),

3,5-dihydroxy-6-(3,7-dimethyl-1-oxooctyl)-2,2,4-tris(3-methyl-2-butenyl)cyclohexa-3,5-dienone(Compound No. 22),

2,4-bis(3-methyl-2-butenyl)-6-(benzoyl)-2,3,5-trihydroxycyclohexa-3,5-dienone(Compound No. 32),

2,4-dimethyl-6-(3-methyl-1-oxobutyl)-2,3,5-trihydroxycyclohexa-3,5-dienone(Compound No. 31),

2,4-bisbenzyl-6-(3-methyl-1-oxobutyl)-2,3,5-trihydroxycyclohexa-3,5-dienone(Compound No. 33),

3,5-dihydroxy-6-(phenylacetyl)-2,2,4-tris(3-methyl-2-butenyl)cyclohexa-3,5-dienone(Compound No. 40),

3,5-dihydroxy-6-(phenylacetyl)-2,2-bis(3-methyl-2-butenyl)cyclohexa-3,5-dienone(Compound 41),

3,5-dihydroxy-6-(phenylacetyl)-2,2,4-tris(3,7-dimethyl-2,6-octadienyl)cyclohexa-3,5-dienone(Compound No. 44), and

3,5-dihydroxy-6-(phenylacetyl)-2,2-bis(3,7-dimethyl-2,6-octadienyl)cyclohexa-3,5-dienone(Compound No. 45) may be cited.

The compound of this invention may form a salt with such an inorganicbase as the hydroxide of an alkali metal or such an organic base asorganic amine, may form a solvation product with such a solvent aswater.

In the compounds represented by the general formula (I), those having2-propyl group, 2-methylpropyl group, or 2-butyl group for R₁ and3-methyl-2-butenyl group for each of R₂ and R₃ are the substances whichare known to be contained in the hops as the precursor of the α acidindicated as the substance (XIII) having the aforementioned activity torepress osteolysis (R. Stevens, Chemical Reviews, 1967, 19 refers).

In the compounds represented by the general formula (I) or (IV), thosehaving 2-propyl group, 2-methylpropyl group, or 2-butyl group for R₁ and3-methyl-2-butenyl group or 3-methylbutyl group for each of R₂ and R₃have been found by assay to possess an antimicroorganic activity as ahop-related compound (S. Mizobuchi and Y. Sato, Agric. Biol. Chem., 49,399 (1985) refers).

The fact that the series of compounds represented by any one of thegeneral formulas (I)-(XII) as proposed by the present invention exhibita powerful activity to repress osteolysis, however, has never been knownto the art and it has been discovered for the first time by the presentinventors.

This invention, therefore, relates to medicinal compositions whichcontain compounds represented by any one of the general formulas(VII)-(XII) mentioned above or one or more pharmaceutically acceptablesalts thereof as an active principle. The medicinal compositions of thisinvention are allowed to contain a varying pharmaceutically acceptablecarrier.

The medicinal compositions of this invention possess an activity toinhibit osteolysis and, therefore, are useful as a preventive andtherapeutic agent for diseases affecting bone and cartilage.

The term “bone and cartilage disease” as used in this invention meansosteolytic diseases such as, for example, malignant hypercalcemia,Paget's disease, and osteoporosis and diseases accompanying chondraldegeneration and necrosis such as, for example, osteoarthritis apt toattack knees, shoulders, and hip joints, femoral head necrosis, andrheumatoid arthritis.

The polyhydroxyphenol derivatives represented by the general formulas(I)-(VI) of the present invention and the medicinal compositionsrepresented by the general formulas (VII)-(XII) of the present inventioncan be produced by the process of the reactions shown in Table 1 below.

The method for production shown in Table 1 will be describedspecifically.

First Step

This step consists in effecting acylation of a polyhydroxybenzene underthe Friedel-Crafts reaction conditions. The polyhydroxybenzenes (a) and(b) are easily available commercially and the polyhydroxybenzene (c) canbe manufactured from picric acid by the method proposed by Ohara et al.(Junichi Onodera and Heitaro Ohara, Journal of the Chemical Society ofJapan, 1973, 1808 refers). As concrete examples of the acylating agent(RCOX) to be used in this step, acetyl chloride, acetyl bromide, aceticanhydride, butyryl chloride, butyryl bromide, butyric anhydride,isobutyryl chloride, isobutyryl bromide, isobutyric anhydride, 2-butyrylchloride, 2-butyryl bromide, 2-butyric anhydride, isovaleryl chloride,isovaleryl bromide, isovaleric anhydride, 3,7-dimethyl octanoylchloride, 3,7-dimethyl octanoyl bromide, 3,7-dimethyl octanoicanhydride, phenylacetyl chloride, phenylacetyl bromide, phenylaceticanhydride, benzoyl chloride, benzoyl bromide, and benzoic anhydride maybe cited. As concrete examples of the acid catalyst to be used in thereaction, the reagents which are generally used in the Friedel-Craftsreaction such as aluminum bromide, aluminum chloride, antimony chloride,iron chloride, titanium chloride, tin chloride, bismuth chloride, zincchloride, boron fluoride, hydrogen fluoride, sulfuric acid, andpolyphosphoric acid may be cited. Among other reagents cited above,aluminum chloride is used particularly advantageously. The acid catalystis used in an amount in the approximate range of 1-3 mols. The reactionis carried out in a solvent. As concrete examples of the solvent usedfor the reaction, nitromethane, nitrobenzene, carbon disulfide,dichloromethane, carbon tetrachloride, and 1,2-dichloroethane may becited. From the viewpoint of solubility, for example, nitrobenzene or amixture of nitrobenzene with carbon disulfide is advantageously used.

A-1

A-2

A-3

B-1

B-2

B-3

C

Though the reaction temperature is in the range of 0° C.-150° C., thereaction proceeds thoroughly at room temperature. The compounds (d),(e), and (f) which are produced by the step described above are used inthe next step.

Second Step

This step consists in introducing an alkyl group or an alkenyl groupinto the acylated polyhydroxybenzene (d), (e), or (f). The reaction ofthis step can be effectively carried out under the basic or the acidicconditions.

(i) Reaction Under Basic Conditions

Under this condition, the acylated polyhydroxybenzene (d), (e), or (f)is converted into a corresponding salt by the reaction of a base and theresultant salt is reacted on by an alkylating agent or alkenylatingagent. As concrete examples of the base to be used herein, alkali metalhydroxides such as sodium hydroxide and potassium hydroxide, alkalimetal alkoxides such as sodium methoxide, potassium methoxide, sodiumethoxide, potassium ethoxide, sodium t-butoxide, and potassiumt-butoxide, alkali metal hydrides such as sodium hydride, potassiumhydride, and lithium hydride, alkyl lithium compounds such as methyllithium, n-butyl lithium, and phenyl lithium, and aryl lithium compoundsmay be cited. The reaction is carried out in a solvent. As concreteexamples of the solvent, water, alcohols such as methanol, ethanol, andt-butanol, ethers such as ethyl ether, isopropyl ether, tetrahydrofuran,and 1,4-dioxane, dimethylsulfoxide, N,N-dimethylformamide andN-methylpyrrolidone, and aromatic compounds such as benzene and toluenemay be cited. The solvent is properly selected to suit the character ofthe base to be used. As concrete examples of the alkylating agentmentioned above, methyl iodide, bromoethane, 1- or 2-bromopropane, 1- or2-chloropropane, 1- or 2-bromobutane, 2-methyl-1-bromopropane,1-bromopentane, 2-chloropentane, 3-methyl-1-bromobutane, 1-bromooctane,1-chlorooctane, benzyl bromide, benzyl chloride, and bromomethylthiophene may be cited. As concrete examples of the alkenylating agentmentioned above, allyl bromide, allyl chloride, 1-bromo-2-butene,1-chloro-2-butene, 3-methyl-1-bromo-2-butene,3-methyl-1-chloro-2-butene, 3,7-dimethyl-1-bromo-2,6-octadiene, and3,7-dimethyl-1-chloro-2,6-octadiene may be cited.

(ii) Reaction Under Acidic Conditions

Though this reaction can be carried out under the standardFriedel-Crafts conditions which are used in the first step mentionedabove, it is advantageously carried out in ethyl ether, 1,4-dioxane, ormethylene chloride by using boron fluorideether (BF3-Et2) (E. Collinsand P. V. R. Shannon, J. Chem. Soc., Perkin Trans., 1, 1973, 419.refers). As concrete examples of the alkylating agent to be used herein,saturated alcohols such as methanol, ethanol, butanol, 3-methyl butanol,pentanol, and decanol, and allyl alcohols such as allyl alcohol,2-butenol, 3-methyl-2-butenol, and 3,7-dimethyl-2,6-octadienol may becited.

By this step, an acyl fluoroglucinol derivative and an acyldihydroxycyclohexadienone derivative of this invention are obtained fromthe compound (d), an acyl hydroxyhydroquinone derivative of thisinvention is obtained from the compound (e), and an acyldihydroxycyclohexadienone derivative of this invention is obtained fromthe compound (f).

Third Step

This step consists in reducing the double bond of the allyl derivative(I-3) produced at the second step and consequently producing an alkylderivative (I-4). Though the standard method for reducing a double bondis utilized at the present step, the method resorting to catalytichydrogenation is used advantageously. The catalysts usable for thecatalytic hydrogenation include platinum oxide, palladium-carbon, andrhodium-carbon, for example. As concrete examples of the solvent whichis used advantageously herein, alcohols such as methanol and ethanol andesters such as ethyl acetate and butyl acetate may be cited. Though thereaction temperature is in the range of 0° C.-100° C., the reaction isadvantageously performed at room temperature.

The polyhydroxyphenol derivative produced as described above was testedfor activity to inhibit osteolysis by the pit formation assay method. Itwas consequently found to exhibit inhibition of osteolysis at anoutstanding ratio in a concentration of 1×10⁻⁵ M (Refer Example 26 andTables 2 and 3 which will be described herein below.).

Though the clinical dosage of the compound of this invention depends onsuch factors as the method of administration, the status of disease, andthe condition of a patient, it is generally in the range of 0.1 g-2 gper adult per day (about 1.5 mg-30 mg/Kg/day). The administration ofthis compound is attainable intravenously, intramuscularly, orally, andper rectum. The intravenous administration may be effected by dripphleboclysis besides the standard intravenous injection. The medicinecontaining the compound of this invention is produced by the standardmethod using standard excipient and additives.

The medicine for injection can be produced, for example, in the form ofa powdery preparation fit for injection. In this case, the preparationcan be obtained by solving the compound in water incorporating thereinone or more suitable water-soluble excipients selected from amongmannitol, sucrose, lactose, maltose, glucose, and fructose, dispensingthe resultant solution in vials or ampoules, freeze drying the solutionin the containers, and hermetically sealing the containers. The medicinefor oral administration can be obtained in the standard forms oftablets, capsules, granules, fine particles, and powder and in anintestinally soluble preparation as well.

The intestinally soluble preparation can be obtained by molding thecompound into tablets, granules, fine particles, etc., when necessary incombination with additives including a lubricant such as, for example,mannitol, sucrose, lactose, maltose, starch, silicic anhydride, orcalcium phosphate, a binding agent such as, for example, carboxymethylcellulose, methyl cellulose, gelatin, or gum arabic, and a disintegratorsuch as, for example, carboxymethyl cellulose calcium, and then coatingthe molded particles with one or more intestinally soluble basesselected from among cellulose acetophthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl cellulose acetyl succinate,polyvinyl alcohol phthalate, styrene, maleic anhydride copolymer,styrene-maleic acid copolymer, methyl methacrylate-methacrylic acidcopolymer, and methyl acrylate-methacrylic acid copolymer, whennecessary in combination with a coloring agent such as, for example,titanium oxide. The intestinally soluble granules or fine particles maybe packed in capsules and used as capsuled medicines. Otherwise, thecapsuled medicines produced by the standard method may be vested withintestinal solubility by being coated with the intestinally soluble basementioned above. Alternatively, an intestinally soluble capsuledmedicine may be obtained by using capsules which are made solely of theintestinally soluble base exclusively or in combination with gelatin.

The suppository can be obtained by homogeneously blending the compoundwith an oleophilic base such as, for example, a semisynthetic baseprepared by mixing cacao butter or fatty acid triglyceride with fattyacid monoglyceride or fatty acid diglyceride at a varying ratio and ahydrophilic base such as, for example, polyethylene glycol orglycerogelatin and molding the resultant blend in a die.

The polyhydroxyphenol derivative which is provided by this inventionpossesses a powerful activity to inhibit osteolysis and, therefore, canbe utilized as a preventive and therapeutic agent for diseases affectingbone and cartilage.

EXAMPLES

Now, this invention will be described more specifically below with theaid of referential examples, examples, and test examples, which aremeant to be illustrative of and not limited in any respect of thepresent invention.

Referential Example 1

Synthesis of (2-propyl)(2,4,6-trihydroxyphenyl) ketone (4)

In a vessel fitted with a calcium chloride tube, 12.61 g (100.0 mmol) of1,3,5-trihydroxybenzene (1) was suspended on a mixture of 35 ml ofnitrobenzene and 45 ml of carbon disulfide and they were stirred. To themixture, 40.0 g (300 mmol, 3.00 equivalents) of granular aluminumchloride was added piecemeal at room temperature. They were stirred forone hour and a nitrobenzene (10.0 ml) solution of 10.66 g (100.0 mmol,1.000 equivalent) of isobutyryl chloride was slowly added dropwise tothe mixture. After about 5 hours, the reaction mixture was poured into acold 2 M hydrochloric acid (500 ml) solution to induce decomposition ofaluminum salt and then was extracted from ether. The organic layer waswashed with water and distilled off ether under a reduced pressure. Tothis was added a large amount of water and water was distilled underreduced pressure to remove nitrobenzene solvent by steam distillationmethod. The residue was dissolved in ether, washed with saturated brine,dried over sodium sulfate, and distilled under a reduced pressure toremove the solvent and obtain 21.7 g of a crude reaction product. Byrecrystallization of the crude product from petroleum ether-methylenechloride (1:1), 17.1 g (yield 87.2%) of the product (4) was obtained inthe form of light yellow powdery crystals.

1HNMR δ (TMS): 1.10 (6H, d, J=7.0 Hz), 3.92 (1H, sept, J=7.0 Hz), 5.83(2H, s), 9.93 (1H, bs), 12.1 (2H, bs).

Referential Example 2

Synthesis of (2-methylpropyl) (2,4,6-trihydroxyphenyl) ketone (5)

A crude reaction product was obtained by repeating the procedure ofReferential Example 1 while using 12.06 g (100.0 mmol) of isovalerylchloride instead. The crude product was recrystallized from petroleumether to obtain 16.7 g (yield 76.9%) of the compound (5) in the form oflightly colored fine powder crystals.

1HNMR δ (TMS): 0.95 (6H, d, J=6.6 Hz), 2.21 (1H, sept, J=6.6), 2.90 (2H,d, J=6.6 Hz), 5.86 (2H, s), 9.86 (1H, s), 12.01 (2H, s).

Example 1

Synthesis of (2,6-dimethylheptyl) (2,4,6-trihydroxyphenyl) ketone (6)

Under the atmosphere of nitrogen, a solvent mixture of 27 ml ofnitrobenzene and 23 ml of carbon disulfide was added to 6.613 g (52.4mmol) of 1,3,5-trihydroxybenzene (1). To the mixture, 21 g (157.2 mmol,3 equivalents) of granular aluminum chloride was added cooling with iceand stirred for two hours. Into the mixture thus formed, was added anitrobenzene (8 ml) solution of 10.87 g (57.0 mmol, 1.09 equivalents) of3,7-dimethyl-octanoyl chloride dropwise and were stirred at roomtemperature for 21 hours. The reaction mixture was poured into a colddilute hydrochloric acid solution prepared by adding 5 ml ofconcentrated hydrochloric acid to 200 ml of ice and stirred andextracted from ether. The organic layer was washed with saturated brine,dried over sodium sulfate, and distilled under a reduced pressure toremove the solvent. To the residue of distillation, a large volume ofwater was added and were distilled under reduced pressure to removenitrobenzene solvent by steam distillation method. The residue wasextracted from ether, washed with saturated brine, dried over sodiumsulfate, and distilled under a reduced pressure to remove the solventand obtain a crude reaction product. By subjecting the crude product tosilica gel column chromatography (using 100 g of Wako Gel C-200, elutionwith hexane:ethyl acetate=7:3), 9.25 g of (2,4,6-trihydroxyphenyl)(2,6-dimethylheptyl) ketone (6) was obtained in the form of an oilysubstance.

1HNMR δ (TMS): 0.85 (6H, d, J=6.2 Hz), 0.96 (3H, d, J=6.6 Hz), 1.4 (7H,m), 2.10 (1H, m), 3.00 (2H, m), 6.02 (2H, s). MS (FAB) m/z 281 (M+1)+.

Example 2

Synthesis of (2-methylpropyl) (2,4,5-trihydroxyphenyl) ketone (7)

In a vessel fitted with a calcium chloride tube, 12.61 g (100.0 mmol) ofhydroxyhydroquinone (2) was suspended in 110 ml of nitrobenzene andstirred at room temperature. Into this, 40.0 g (300 mmol, 3.00equivalents) of granular aluminum chloride was added piecemeal. Theywere further stirred for one hour and then 12.06 g (100.0 mmol, 1.00equivalent) of isovaleryl chloride was slowly added dropwise. As thereaction mixture became a reddish purple amorphous solid 10 hours afterthe addition, it was mechanically crushed into fine fragments. The finefragments were poured into 500 ml of a cold 2 M hydrochloric acidsolution, stirred for 30 minutes, and extracted from ether. The etherlayer was washed with water, distilled to remove the solvent, combinedwith a large volume of water, and distilled water under reduced pressureto remove nitrobenzene by steam distillation method. The residue of thedistillation was dissolved in ether, washed with saturated brine, driedover sodium sulfate, distilled under a reduced pressure to remove etherand obtain a crude reaction product. By recrystallizing the crudeproduct from hexane-petroleum ether (2:1), 18.3 g (yield 86.6%) of theproduct (7) was obtained in the form of reddish purple crystals of thinneedles.

1HNMR δ (TMS): 0.96 (6H, d, J=6.6 Hz), 2.18 (1H, sept, J=6.6 Hz), 2.69(2H, d, J=6.9 Hz), 6.50 (1H, s), 7.17 (1H, s), 8.6 (2H, bs), 10.1 (1H,bs).

Referential Example 3

Synthesis of (2-propyl) (2,3,4,6-tetrahydroxyphenyl) ketone (8)

In a vessel fitted with a calcium chloride tube, 1.00 g (7.04 mmol) of1,2,3,5-tetrahydroxybenzene (3) was dissolved in 20 ml of nitrobenzeneand stirred. Into the stirred mixture, 2.82 g (21.1 mmol, 3.00equivalents) of granular aluminum chloride was added piecemeal andstirred. One hour thereafter, a nitrobenzene (5.0 ml) solution of 0.750g (7.04 mmol, 1.00 equivalent) of isobutyryl chloride was addeddropwise. Ten hours thereafter, the reaction solution was poured into100 ml of cold 2 M hydrochloric acid solution, stirred for 30 minutes,and then extracted from ether. The ether layer was washed with water,distilled to remove ether, combined with a large volume of water, anddistilled water under reduced pressure to remove nitrobenzene by steamdistillation. The residue was extracted from ether, washed withsaturated brine, dried over sodium sulfate, and distilled under areduced pressure to remove the solvent and obtain 1.38 g of crudeproduct. By purifying the crude product by column chromatography (SiO₂,20 g of Wako Gel C-300, hexane:ether=1:1), 441 mg (yield 65.9%) of theproduct (8) was obtained in the form of yellow powder crystals.

1HNMR δ (TMS): 1.10 (6H, d, J=6.7 Hz), 3.95 (1H, sept, J=6.7 Hz), 5.90(1H, s), 8.62 (bs).

Referential Example 4

Synthesis of (2-methylpropyl) (2,3,4,6-tetrahydroxyphenyl) ketone (9)

Under an atmosphere of argon, 4.28 g (30.14 mmol) of1,2,3,5-tetrahydroxybenzene (3) was dissolved by stirring in 70 ml ofnitrobenzene. The solution was cooled with water. To the cold solution,16.1 g (120.56 mmol, 4.00 equivalents) of granular aluminum chloride wasadded piecemeal and stirred. To the stirred mixture, 3.67 ml (30.1 mmol,1.00 equivalent) of isovaleryl chloride was added dropwise. After 5hours, the reaction solution was poured into 100 ml of a cold.2 Mhydrochloric acid solution, stirred for 20 minutes, and extracted fromether. The organic layer was washed with water, distilled to removeether, combined with a large volume of water, and distilled underreduced pressure to remove nitrobenzene. The residue was extracted fromether, washed with saturated brine, dried over sodium sulfate, anddistilled under a reduced pressure to obtain a crude reaction product.By purifying the crude product by silica gel column chromatography (300g of Wako Gel C-200, hexane:ethyl acetate=2:1), 1.85 g (yield 27.2%) ofthe product (9) was obtained in the form of yellow powder crystals.

1HNMR δ (TMS): 0.97 (6H, d, J=6.6 Hz), 2.25 (1H, m), 2.96 (2H, d, J=7.0Hz), 6.02 (1H, s), 6.9 (1H, brs), 8.5 (1H, brs), 9.79 (1H, brs), 11.76(1H, brs); LR-MS (E1, 70V, 300 μA) 226 (M⁺) , 211, 193, 169 (base) , 69.

Referential Example 5

Synthesis of (2,3,4,6-tetrahydroxyphenyl) phenyl ketone (10)

Under a stream of argon, 1.30 g (9.15 mmol) of1,2,3,5-tetrahydroxyphenol (3) was suspended in 13 ml of ether and 0.935ml (9.15 mmol, 1.00 equivalent) of benzonitrile was added to thesuspension with stirring. The resultant mixture was cooled with icewater and 0.624 g (4.57 mmol, 0.50 equivalent) of zinc chloride wasadded and they were stirred at room temperature for 6 hours by bubblinghydrogen chloride gas throughout. The aeration of the mixture with thegas was stopped and the mixture was left standing at 4° C. for 13 hours.From the tarry precipitates consequently formed was removed the etherlayer by decantation. The precipitates were stirred in an ice bath and39 ml of water was added and were then refluxed for 2 hours. The productof reflux was filtered while kept in hot and stand still to form redbrown from the filtrate. By dissolving the crystals again in ether,filtering off insolubles from the solution, and concentrating, 0.97 g(yield 45.9%) of the product (10) was obtained in the form of orangepowder crystals.

1H-NMR δ (TMS): 6.03 (1H, s), 7.33-7.66 (6H, m), 8.0-11.0 (3H, br);13C-NMR δ (TMS): 95.3, 104.3, 125.0, 127.5, 128.2, 130.7, 141.8, 149.5,153.8, 155.8, 198.9; LR-MS (E1, 70V, 300 μA) 246 (M⁺, base), 168, 140,105, 77, 69.

Referential Example 6

Synthesis of methyl (2,3,4,6-tetrahydroxyphenyl) ketone (11)

Under a stream of argon, 2.00 g (14.08 mmol) of1,2,3,5-tetrahydroxyphenol (3) and 20 ml of ether were placed to form asuspension and 1.00 g (24.3 mmol, 1.73 equivalents) of acetonitrile wasadded to the suspension. While the resultant mixture was cooled with icewater, 0.70 g (5.14 mmol, 0.36 equivalent) of zinc chloride was added tothe mixture and hydrogen chloride gas was bubbled at room temperaturefor four hours with stirring. The aeration of the mixture with the gaswas stopped and the aerated mixture was left standing still at 4° C. for13 hours. The ether layer was removed by decantation from the tarryprecipitates consequently formed. The precipitates were stirred in anice bath and 60 ml of water was added-to the stirred precipitates andthey were heated under reflux for 4 hours. The product of the reflux,after adding a small amount of active carbon, was filtered while kept inhot. From the filtrate, yellow crystals were obtained as precipitates.By dissolving the crystals again in ether, removing the insoluble byfilteration, and then concentrating the filtrate, 0.82 g (yield 31.8%)of the product (11) was obtained in the form of yellow platelikecrystals.

1H-NMR (90 MHz, d₆-DMSO) δ (TMS): 2.61 (3H, s), 5.93 (1H, s), 7.0 (1H,brs), 9.5 (1H, brs), 11.76 (1H, s); LR-MS (E1, 70V, 300 μA) 184 (M⁺),169 (base), 69.

Example 3

Synthesis of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl}(2-propyl) ketone (12),2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(2-methyl-1-oxopropyl)cyclohexa-3,5-dienone(13), and {3-(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (2-propyl)ketone (14)

Under an atmosphere of nitrogen, 600 mg (15.0 mmol, 3.00 equivalents) ofan oily 60% sodium hydride was washed with dry hexane to removeparaffin. In this solution, 20 ml of dimethyl sulfoxide was placed andstirred at room temperature. To the resultant mixture, a dimethylsulfoxide (5.0 ml) solution of 981 mg (5.00 mmol) of (2-propyl)(2,4,6-trihydroxyphenyl) ketone (4) was added over a period of 15minutes and stirred for 30 minutes. Then, a dimethyl sulfoxide (5.0 ml)solution of 1.43 g (10.0 mmol, 2.00 equivalents) of1-bromo-3-methyl-2-butene was added dropwise over a period of 30minutes. The resultant mixture was stirred at room temperature for 14hours. The mixture was poured into 50 ml of a cold 2 M hydrochloric acidsolution and extracted from ether. The ether layer was washed withsaturated brine, dried over sodium sulfate, and distilled to remove thesolvent and obtain 1.580 g of a crude product in the form of red oilysubstance. The crude product was separated by silica gel columnchromatography (65 g of Wako Gel C-200, benzene:ethyl acetate=9:1) into(a) 239 mg of a brown viscous oily substance, (b) 342 mg of an orangecolor viscous oily substance, and (c) 206 mg of a yellow crystallinesubstance sequentially in the order of elution as indexed by the thinlayer chromatography. The fraction (a) was further purified by columnchromatography (15 g of Wako Gel C-300, petroleum ether:ether=9:1) toobtain 58 mg of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl}(2-propyl) ketone (12) in the form of yellow crystals.

1HNMR δ (TMS): 1.16 (6H, d, J=6.6 Hz), 1.78 (6H, s), 1.83 (6H, s), 3.38(4H, bd), 3.99 (1H, sept, J=6.6 Hz), 5.22 (2H, m), 6.29 (1H, s), 10.14(2H, s).

The fraction (b) was similarly purified by column chromatography (18 gof Wako Gel C-300, petroleum ether:ether=7:3) to obtain 197 mg of2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(2-methyl-1-oxopropyl)cyclohexa-3,5-dienone(13) in the form of a yellow viscous substance.

1HNMR δ (TMS): 1.17 (6H, d, J=6.8 Hz), 1.58 (12H, bs), 2.62 (4H, bd),3.98 (1H, sept, J=6.8 Hz), 4.85 (2H, m), 5.96 (1H, s).

The fraction (c) was treated by column chromatography (15 g of Wako GelC-300, petroleum ether:ether=2:1) to obtain 110 mg of{3-(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (2-propyl) ketone (14)in the form of yellow crystals.

1HNMR δ (TMS): 1.13 (6H, d, J=6.6 Hz), 1.66 (3H, s), 1.76 (3H, s), 3.20(2H, bd), 5.21 (1H, m), 6.02 (1H, s).

Example 4

Synthesis of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl}(2-propyl) ketone (12) and2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(2-methyl-1-oxopropyl)-cyclohexa-3,5-dienone(13)

Under an atmosphere of nitrogen, 981 mg (5.00 mmol) of(2,4,6-trihydroxyphenyl) (2-propyl) ketone (4) was dissolved in 10.0 mlof dioxane, cooled with cold water at about 10° C., and stirred. Intothe stirred solution, 554 ml (639 mg, 4.50 mmol, 0.900 equivalent) ofboron trifluorideether complex was added by the use of a microsyringe.The resultant mixture was further stirred for 15 minutes and then adioxane (9 ml) solution of 861 mg of 3-methyl-2-butenol was slowly addeddropwise. After four hours, the reaction solution was poured into 100 mlof ether. The ether layer was washed sequentially with a saturatedaqueous sodium hydrogen carbonate solution and saturated brine and driedover sodium sulfate. The produced solution was distilled under a reducedpressure to remove the solvent and obtain 1.76 g of a crude product inthe form of a red viscous oily substance. The crude product was treatedby silica gel column chromatography (50 g of Wako Gel C-300, and elutedsequentially with 200 ml each of petroleum ether:ether at varyingratios=9:1, 7:3, and 5:5) to isolate 417 mg of{3-(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (2-propyl) ketone (23)and 338 mg of2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(2-methyl-1-oxopropyl)cyclohexa-3,5-dienone (13).

Example 5

Synthesis of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl}(2-methylpropyl) ketone (15),3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-2,2,4-tris(3-methyl-2-butenyl)cyclohexa-3,5-dienone(16), and2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(3-methyl-1-oxobutyl)cyclohexa-3,5-dianone(17)

Under an atmosphere of nitrogen, 441 mg (11.1 mmol, 2.06 equivalents) ofan oily 60% sodium hydride was washed with dry hexane to removeparaffin. To this was added 6.0 ml of dry methanol cooling with ice andstirred. Then, a methanol (6.0 ml) solution of 1.135 g (5.400 mmol) of(2-methylpropyl) (2,4,6-trihydroxyphenyl) ketone (5) was added dropwiseto the solution. Further, a methanol (5.0 ml) solution of 1.205 g (11.52mmol, 2.130 equivalents) of 1-chloro-3-methyl-2-butene was slowly addeddropwise. The mixture was stirred cooling with ice for 1.5 hours, thenadded 50 ml of a saturated aqueous ammonium chloride solution, andextracted from ether. The ether layer was washed with saturated brine,dried over sodium sulfate, and distilled under a reduced pressure toremove the solvent and obtain 1.752 g of a crude product in the form ofa red viscous oily substance. This crude product was subjected to silicagel column chromatography (40 g of Wako Gel C-300 and elutedsequentially with 200 ml each of petroleum ether:ether at varyingratios=19:1, 18:2, 17:3, and 16:4). From the eluate of the column,various fractions were sequentially obtained. As the first fraction, 160mg of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl}(2-methylpropyl) ketone (15) was obtained in the form of light yellowcrystals shaped fine needles.

1HNMR δ (TMS): 0.96 (6H, d. J=6.6 Hz), 1.78 (6H, s), 1.83 (6H, s), 2.26(1H, sept, J=6.6 Hz), 2.94 (2H, d, J=6.6 Hz), 3.37 (4H, d, J=6.2 Hz),5.22 (2H, m), 6.26 (1H, bs), 10.12 (2H, bs).

As the second fraction, 549 mg of3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-2,2,4-tris(3-methyl-2-butenyl)-cyclohexa-3,5-dienone(16) in the form of yellow crystals.

1HNMR δ (TMS): 0.96 (6H, d, J=6.6 Hz), 1.56 (15H, s), 1.78 (3H, s), 2.11(1H, sept, J=6.6 Hz), 2.60 (4H, m), 2.92 (2H, d, J=6.9 Hz), 3.19 (2H, d,J=7.3 Hz), 4.79 (2H, m), 5.11 (1H, m).

As the third fraction, 259 mg of2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(3-methyl-1-oxobutyl)cyclohexa-3,5-dienone(17) was obtained in the form of a yellow viscous oily substance.

1HNMR δ (TMS): 0.99 (6H, d, J=6.6 Hz), 1.57 (12H, bs), 2.16 (1H, sept,J=6.6 Hz), 2,62 (4H, m), 2.95 (2H, d, J=6.9 Hz), 4.84 (2H, m), 5.65 (1H,s).

Example 6

Synthesis of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl}(2-methylpropyl) ketone (15),3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-2,2,4-tris(3-methyl-2-butenyl)cyclohexa-3,5-dienone(16), and2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(3-methyl-1-oxobutylcyclohexa-3,5-dienone(17)

Under an atmosphere of nitrogen, 2.244 g (20.00 mmol, 2.000 equivalents)of potassium t-butoxide was dissolved in 20.0 ml of dry methanol and theresultant solution was stirred cooling with ice. To the solution, amethanol (10.0 ml) solution of 2.102 g (10.00 mmol) of (2-methylpropyl)(2,4,6-trihydroxyphenyl) ketone (5) was added dropwise and then amethanol (15.0 ml) solution of 2.861 g (20.00 mmol, 2.000 equivalents)of 1-bromo-3-methyl-2-butene was further added slowly. The mixture wasstirred cooling with ice for one hour and then at room temperature fortwo hours and then extracted by ether. The organic layer was washed withsaturated brine, dried over sodium sulfate, and distilled under areduced pressure to remove the solvent and obtain 2.932 g of a crudeproduct in the form of a red viscous oily substance. The crude productwas subjected to silica gel column chromatography (100 g of Wako GelC-300 and eluted sequentially with 400 ml each of petroleum ether:etherat varying ratios=9:1, 8:2, 7:3, and 6:4). Consequently, the isolationof 117 mg of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl}(2-methylpropyl) ketone (15), 153 mg of3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-2,2,4-tris(3-methyl-2-butenyl)-cyclohexa-3,5-dienone(16), and 235 mg of2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(3-methyl-1-oxobutyl)cyclohexa-3,5-dienone(17) was confirmed, with a thin layer chromatography as an index.

Example 7

Synthesis of2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(3-methyl-1-oxobutyl)cyclohexa-3,5-dienone(17) and {3-(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl}(2-methylpropyl) ketone (18)

Under an atmosphere of nitrogen, 1.47 g (7.00 mmol) of (2-methylpropyl)(2,4,6-trihydroxyphenyl) ketone (5) was dissolved in 14.0 ml of drydioxane and the solution was stirred in cold water (10° C.). To thesolution, 690 ml (795 mg, 5.60 mmol, 0.80 equivalent) of borontrifluoride ether complex was added by the use of a microsyringe andthen a dioxane (10.0 ml) solution of 1.21 g (14.0 mmol, 2.00equivalents) of 3-methyl-2-butenol was added dropwise over a period ofabout 0.5 hour. The resultant mixture was stirred at room temperaturefor 14 hours and then was added 140 ml of ether. The organic layer waswashed sequentially with a saturated aqueous sodium hydrogen carbonatesolution and then with saturated brine, dried over sodium sulfate, anddistilled under a reduced pressure to remove the solvent and obtain 2.93g of a crude product in the form of a red viscous oily substance. Thecrude product was subjected to silica gel column chromatography (100 gof Wako Gel C-300 and eluted sequentially with 200 ml each of petroleumether:ether at varying ratios=9:1, 8:2, 7:3, 6:4, and 5:5). With a thinlayer chromatography as an index, as the first fraction, 427 mg of anoily substance was gathered and subjected again to silica gel columnchromatography (17 g of Wako Gel C-300, eluted with petroleum etherether=8:2) to isolate 311 mg of2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(3-methyl-1-oxobutyl)cyclohexa-3,5-dienone(17).

The subsequent fraction of eluate, i.e. 613 mg of an oily substance, wassubjected again to silica gel column chromatography (21 g of Wako GelC-300, and eluted with petroleum ether:ether=7:3) to obtain 459 mg of{3-(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl) (2-methylpropyl) ketone(18) in the form of light yellow crystals.

1HNMR δ (TMS): 0.96 (6H, d, J=6.6 Hz), 1.71 (3H, s), 1.77 (3H, s), 2.23(1H, sept, J=6.6 Hz), 2.95 (2H, d, J=6.3 Hz), 3.31 (2H, bd), 5.22 (1H,m), 5.95 (1H, m). cl Example 8

Synthesis of{3,5-bis(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl}(2-methylpropyl) ketone (19),3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-2,2,4-tris(3,7-dimethyl-2,6-octadienyl)cyclohexa-3,5-dienone(20), and2,2-bis(3,7-dimethyl-2,6-octadienyl)-3,5-dihydroxy-6-(2-methyl-1-oxobutyl)cychlohexa-3,5-dienone(21)

Under an atmosphere of nitrogen, 400 mg (10.0 mmol, 2.00 equivalents) ofan oily paraffin dispersion of 60% sodium hydride was washed withhexane. A sodium methoxide solution was prepared by adding 10.0 ml ofdry methanol to the resultant solution cooling with ice. To this, wasadded a methanol (5.0 ml) solution of 1.051 g (5.000 mmol) of(2,4,6-trihydroxyphenyl) (2-methylpropyl) ketone (5) dropwise and then amethanol (8.0 ml) solution of 1.727 g (10.0 mmol, 2.000 equivalents) of1-chloro-3,7-dimethyl-2,6-octadiene was added dropwise over a period of0.5 hour. The mixture was then stirred at room temperature for one hour.The resultant mixture was combined with 40 ml of a saturated aqueousammonium chloride solution and extracted by ether. The extract waswashed with saturated brine, dried over sodium sulfate, and distilledunder a reduced pressure to remove the solvent and obtain 2.527 g of acrude product in the form of a red viscous oily substance. The crudeproduct was subjected to silica gel column chromatography (95 g of WakoGel C-300, eluted with 300 ml each of hexane:ether at varyingratios=9:1, 8:2, 7:3, 6:4, and 5:5). The fractions of the eluateseparated, analysed by thin layer chromatography as an index, andproduced

(a) 663 mg of an orange oily substance,

(b) 196 mg of an orange viscous oily substance, and

(c) 218 mg of an orange viscous oily substance.

The fraction (a) was further subjected to silica gel columnchromatography (27 g of Wako Gel C-300, eluted with 150 ml each ofhexane:ether at varying ratios=29:1, 28:2, and 27:3) to isolate 128 mgof (3,5-bis(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxy-phenyl}(2-methylpropyl) ketone (19). 1HNMR δ (TMS): 0.96 (6H, d, J=6.6 Hz),1.60 (9H, s), 1.67 (9H, s), 2.07 (9H, m), 2.95 (2H, d, J=7.2 Hz), 3.39(4H, d, J=9.0 Hz), 5.08 (2H, m), 5.34 (2H, m).

From the fraction (b),3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-2,2,4-tris(3,7-dimethyl-2,6-octadienyl)-cyclohexa-3,5-dianone(20) was obtained.

1HNMR δ (TMS): 0.98 (6H, d, J=6.6 Hz), 1.56 (12H, s), 1.64 (6H, s), 1.91(12H, bs), 2.24 (1H, m), 2.65 (4H, m), 2.94 (2H, d, J=6.8 Hz), 3.45 (2H,d, J)=8.0 Hz), 4.95 (6H, m).

From the fraction (c),2,2-bis(3,7-dimethyl-2,6-octadienyl)-3,5-dihydroxy-6-(2-methyl-1-oxobutyl)-cyclohexa-3,5-dienone(21) was obtained.

1HNMR δ (TMS): 0.97 (6H, d, J=6.6 Hz), 1.59 (bs) and 1.67 (b) (total18H), 1.99 (9H, m), 2.58 (4H, m), 2.96 (2H, d, J=6.8 Hz), 4.99 (4H, m),5.94 (1H, s).

Example 9

Synthesis of3,5-dihydroxy-6-(3,7-dimethyl-1-oxooctyl)-2,2,4-tris(3-methyl-2-butenyl)cyclohexa-3,5-dienone(22) and {3-(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl}(2,6-dimethylheptyl) ketone (23)

To 0.432 g (6.16 mmol, 2.00 equivalents) of potassium methoxide, 1 ml ofdry methanol was added cooling with ice. Then, they were stirred for 15minutes. A methanol (4 ml) solution of 0.864 g (3.08 mmol) of(2,4,6-trihydroxyphenyl) (2,6-dimethylheptyl) ketone (6) was addeddropwise to the solution and continued stirring cooling with ice for 30minutes. To the mixture, 728 ml (6.47 mmol, 2.10 equivalents) of1-chloro-3-methyl-2-butene was added dropwise, stirring at roomtemperature for 3.5 hours. The resultant mixture was combined with 20 mlof a saturated aqueous ammonium chloride solution, extracted by ether,washed with saturated brine, dried over sodium sulfate, and distilledunder a reduced pressure to remove the solvent and obtain a crudeproduct. By subjecting this crude product to silica gel columnchromatography (50 g of Wako Gel C-300 and eluted withhexane:ether=7:3), 0.181 g of3,5-dihydroxy-6-(3,7-dimethyl-1-oxooctyl)-2,2,4-tris(3-methyl-2-butenyl)cyclohexa-3,5-dienone(22) was obtained in the form of an oily substance.

1HNMR δ (TMS): 0.86 (6H, d, J=6.3 Hz), 0.94 (3H, d, J=6.6 Hz), 1.25 (7H,m), 1.57 (12H, s), 2.00 (1H, m), 2.67 (4H, d, J=6.9 Hz), 3.00 (2H, m),4.84 (2H, 6, J=6.9 Hz). MS (EI) m/z 416 (M)⁺.

Further, from the eluate with hexane:ether=6:4, 0.311 g of{3-(3-methyl-2-butenyl-2,4,6-trihydroxyphenyl} (2,6-dimethylheptyl)ketone (23) in the form of an oily substance.

1HNMR δ (TMS): 0.84 (6H, d, J=6.3 Hz), 0.92 (3H, d, J=7.3 Hz), 1.23 (7H,m), 1.76 (bs), 1.81 (bs), (total 6H), 2.10 (1H, m), 2.80 (2H, m), 3.13(2H, m), 3.34 (2H, d, J=7.3 Hz), 5.24 (1H, m), 5.90 (1H, m). MS (EI) m/z348 (M)⁺.

Example 10

Synthesis of2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(3,7-dimethyl-1-oxooctyl)cyclohexa-3,5-dienone(24)

To 0.619 g (8.82 mmol, 2 equivalents) of potassium methoxide, 5 ml ofdry methanol was added cooling with ice and stirred for 15 minutes. Tothis, a methanol (5 ml) solution of 1.536 g (4.41 mmol) of2,4,6-trihydroxyphenyl) (2,6-dimethylheptyl) ketone (6) was addeddropwise and stirred cooling with ice for 30 minutes. Further, 1.093 ml(9.702 mmol, 2.20 equivalents) of 1-chloro-3-methyl-2-butene was addeddropwise and stirred at room temperature for 4 hours. The mixture wascombined with 80 ml of a saturated aqueous ammonium chloride solution,extracted by ether, washed with saturated brine, dried over sodiumsulfate, and distilled under a reduced pressure to remove the solventand obtain a crude product. By subjecting this crude product to silicagel column chromatography (80 g of Wako Gel C-300 and eluted withhexane:ether=99:1, 97:3, and 95:5), 0.305 g of2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(3,7-dimethyl-1-oxooctyl)-cyclohexa-3,5-dienone(24) in the form of an oily substance.

1HNMR δ (TMS): 0.86 (6H, d, J=5.9 Hz), 0.93 (3H, d, J=6.2 Hz), 1.26 (7H,m), 1.57 (bs), 1.79 (bs) (total 18H), 2.00 (1H, m), 2.58 (4H, m), 2.97(2H, m), 3.19 (2H, bd), 4.81 (2H, bt), 5.15 (1H, bt). MS (El) m/z 484(M)⁺.

Example 11

Synthesis of {3,6-bis(3-methyl-2-butenyl)-2,4,5-trihydroxyphenyl}(2-methylpropyl) ketone (25) and{3-(3-methyl-2-butenyl)-2,4,5-trihydroxyphenyl} (2-methylpropyl) ketone(26)

Under an atmosphere of nitrogen, a dioxane (20.0 ml) solution of 2.102 g(10.0 mmol) of (2,4,5-trihydroxyphenyl) (2-methylpropyl) ketone (7) wasstirred cooling with ice. To the solution, 1230 ml (1.420 g, 10.00 mmol,1.000 equivalent) of boron trifluoride ether complex was added and thena dioxane (16.0 ml) solution of 2.584 g (30.0 mmol) of3-methyl-2-butenol was slowly added. The mixture was stirred coolingwith ice for three hours and then left standing at room temperature for14 hours. The mixture was combined with 200 ml of ether. The organiclayer was washed with a saturated aqueous sodium hydrogen carbonatesolution and saturated brine, dried over sodium sulfate, and distilledunder a reduced pressure to remove the solvent and obtain 4.018 g of acrude product in the form of dark red oily substance. By subjecting thiscrude product to silica gel column chromatography (80 g of Wako GelC-300 and eluted with 300 ml each of hexane:ether at varying ratios=9:1,8:2, 7:3, 6:4, and 5:5), 249 mg of{3,6-bis(3-methyl-2-butenyl)-2,4,5-trihydroxyphenyl} (2-methylpropyl)ketone (25) in the form of yellow crystals shaped fine needles.

1HNMR δ (TMS): 0.96 (6H, d, J=6.6 Hz), 1.74 (bs), 1.80 (bs) (total 12H),2.25 (1H, sept, J=6.6 Hz), 2.72 (2H, d, J=7.0 Hz), 3.41 (2H, d, J=7.0Hz), 3.48 (2H, d, J=7.0 Hz), 5.03 (1H, s), 5.03 (1H, m), 5.29 (1H, m),6.30 (1H, s).

As a fraction of higher polarity, 231 mg of{3-(3-methyl-2-butenyl)-2,4,5-trihydroxyphenol} (2-methylpropyl) ketone(26) was isolated.

1HNMR δ (TMS): 0.98 (6H, d, J=6.5 Hz), 1.74 (3H, s), 1.82 (3H, s), 2.25(1H, sept, J=6.5 Hz), 2.69 (2H, d, J=6.8 Hz), 3.43 (2H, d, J=7.0 Hz),5.30 (1H, m), 7.12 (1H, s).

Example 12

Synthesis of {6-(3-methyl-2-butenyl)-2,4,5-trihydroxyphenyl}(2-methylpropyl) ketonemono(3-methyl-2-butenyl) ether (27) and(2,4,5-trihydroxyphenyl) (2-methylpropyl) ketonemono(3-methyl-2-butenyl)ether (28)

Under an atmosphere of nitrogen, 400 mg (10.0 mmol, 2.00 equivalents) ofan oily 60% sodium hydride was washed with dry hexane to removeparaffin. A sodium methoxide solution was prepared by adding 10.0 ml ofdry methanol to the dispersion cooling with ice. To this, a methanol(6.0 ml) solution of 1.051 g (5.000 mmol) of (2,4,5-trihydroxyphenyl)(2-methylpropyl) ketone (7) was added and then a methanol (8.0 ml)solution of 1.046 g (10.00 mmol, 2.000 equivalents) of1-chloro-3-methyl-2-butene was slowly added. The resultant mixture wasstirred at room temperature for two hours. This mixture was combinedwith 200 ml of ether, neutralized with 100 ml of a saturated aqueousammonium chloride solution, washed with saturated brine, dried oversodium sulfate, and distilled under a reduced pressure to remove thesolvent and obtain 1.730 g of a crude product in the form of a redviscous oily substance. This crude product, when subjected to thetreatment of separation by silica gel column chromatography (50 g ofWako Gel C-300, eluted with 200 ml each of petroleum ether:ether atvarying ratios=9:1, 8:2, 7:3, 6:4), afforded 68 mg of{6-(3-methyl-2-butenyl)-2,4,5-trihydroxyphenyl} (2-methylpropyl)ketonemono(3-methyl-2-butenyl) ether (27) in the form of yellow crystalsshaped fine needles.

1HNMR δ (TMS): 0.87 (6H), d, J=6.4 Hz), 1.74 (s), 1.73 (s) (total 12H),2.22 (1H, sept, J=6.4 Hz), 2.79 (2H, d, J=6.6 Hz), 3.56 (2H, d, J=5.6Hz), 4.58 (2H, d, J=6.9 Hz), 5.17 (1H, m), 5.44 (1H, m), 5.44 (1H, s),6.37 (1H, s).

From the fraction of higher polarity, 64 mg of (2,4,5-trihydroxyphenyl)(2-methylpropyl) ketone.mono(3-methyl-2-butenyl) ether (28) in the formof yellow crystals shaped needles.

1HNMR δ (TMS): 0.99 (6H, d, J=6.6 Hz), 1.74 (3H, s), 1.79 (3H, s), 2.75(1H, m), 2.71 (2H,.d, J=6.6 Hz), 4.60 (2H, d, J=6.8 Hz), 5.46 (1H, m),6.44 (1H, s), 7.22 (1H, s).

Example 13

Synthesis of2,4-bis(3-methyl-2-butenyl)-6-(2-methyl-1-oxopropyl)-2,3,5-trihydroxycyclohexa-3,5-dienone(29)

Under an atmosphere of nitrogen, 125 mg (3.12 mmol, 3.00 equivalents) ofan oily 60% sodium hydride was washed with hexane to remove the oilycomponent and then the sodium hydride was suspended on 2.0 ml ofdimethyl sulfoxide cooling with cold water. A dimethyl sulfoxide (1.5ml) solution of 221 mg (1.04 mmol) of (1,2,3,5-tetrahydroxyphenyl)(2-propyl) ketone (8) was added dropwise to the suspension. After themixture was stirred for 30 minutes, a dimethylsulfoxide (1.0 ml)solution of 327 mg (2.29 mmol, 2.20 equivalents) of1-bromo-3-methyl-2-butene was slowly added dropwise to the mixture. Theproduced mixture was stirred at room temperature for one hour, thencombined with 100 ml of ether, and neutralized with a saturated aqueousammonium chloride solution. The ether layer was washed with saturatedbrine, dried over sodium sulfate, distilled under a reduced pressure toremove the solvent and obtained 318 mg of a crude produce in the form ofan orange amorphous solid. The crude product was purified by silica gelcolumn chromatography (10 g of Wako Gel C-300, eluted withhexane:ether=7:3) to isolate 90 mg of2,4-bis(3-methyl-2-butenyl)-6-(2-methyl-1-oxopropyl)-2,3,5-trihydroxycyclohexa-3,5-dienone(29) in the form of a yellow viscous oily substance.

1HNMR δ (TMS): 1.13 (6H, d, J=6.9 Hz), 1.52 (s), 1.67 (s), 1.73 (s)(total 12 H), 2.51 (2H, d, J=7.2 Hz), 3.09 (2H, d, J=7.2 Hz), 3.71 (1H,sept, J=7.2 Hz), 5.00 (1H, m), 5.14 (1H, m).

Example 14

Synthesis of2,4-bis(3-methyl-2-butenyl)-6-(1-oxoethyl)-2,3,5-trihydroxycyclohexa-3,5-dienone(30)

Under a stream of argon, 200 mg (4.89 mmol, 3.00 equivalents) of an oildispersion of 60% sodium hydride was washed with hexane to remove theoil component. While the dispersion and 8.0 ml of dry dimethyl-sulfoxideadded cooling with water were stirred, 300 mg (1.63 mmol) of2-methylpropyl-(2,3,4,6-tetrahydroxyphenyl) ketone (9) was added andstirred for 40 minutes. To the mixture, was added 0.367 ml (3.26 mmol,2.00 equivalents) of 1-chloro-3-methyl-2-butene dropwise and stirred forfour hours. The produced mixture was combined with 4 ml of 2 Mhydrochloric acid solution and extracted by ethyl acetate. The organiclayer was washed with saturated brine, dried over sodium sulfate,concentrated under a reduced pressure, and subjected to silica gelchromatography (100 g of Wako Gel C-200, eluted with benzene:ethylacetate:acetic acid=8:1:0.1) to obtain 242.6 mg (yield 46.5%) of theproduct (30) in the form of yellow powdery crystals.

1H-NMR (90 MHz, CDCl₃) δ (TMS): 1.53-1.73 (12H, m), 2.51 (5H, m), 3.08(2H, d, J=7.5), 5.07 (2H, m), 18.65 (1H, s); LR-MS (EI, 70V, 300 μA) 320(M⁺) 252, 196 (base), 69.

Example 15

Synthesis of2,4-dimethyl-6-(3-methyl-1-oxobutyl)-2,3,5-trihydroxycyclohexa-3,5-dienone(31)

Under a stream of argon, 372 mg (9.30 mmol, 3.00 equivalents) of an oilydispersion of 60% sodium hydride was washed with hexane to remove theoily component. The suspension kept cooled with water and 7.0 ml of drydimethyl sulfoxide added were stirred. To the suspension, 700 mg (3.10mmol) of 2-methylpropyl-(2,3,4,6-tetrahydroxyphenyl) ketone (9) wasadded and stirred for 30 minutes. Further, 0.579 ml (9.30 mmol,equivalent) of methyl iodide was added dropwise to the mixture andstirred for four hours. The resultant mixture was combined with 3 ml of2 M hydrochloric acid solution and 1 ml of an aqueous 10% sodiumthiosulfate solution and extracted by ethyl acetate. The organic layerwas washed with saturated brine, dried over sodium sulfate, concentratedunder a reduced pressure, and subjected to silica gel chromatography (75g of Wako Gel C-200, eluted with carbon tetrachloride:ethylacetate:acetic acid=400:200:5) to obtain 224 mg (yield 28.4%) of theproduct (31) in the form of yellow powdery crystals.

1H-NMR (90 MHz, CDCl₃) δ (TMS): 0.97 (3H, d, J=6.6), 1.01 (3H, d,J=6.6), 1.58 (3H, s), 1.86 (3H, s), 2.15 (1H, m), 2.82 (2H, d, J=7.0),4.45 (1H, brs), 7.42 (1H, brs), 18.92 (1H, s); 13C-NMR (90 MHz, CDCl₃) δ(TMS): 6.9, 22.5, 22.8, 26.7, 30.4, 46.8, 75.7, 104.9, 105.2, 168.9,191.1, 196.4, 201.3; LR-MS (EI, 70V, 300 μA) 254 (M⁺), 237, 211 (base),180, 151, 57.

Example 16

Synthesis of2,4-bis(3-methyl-2-butenyl)-6-benzoyl-2,3,5-trihydroxycyclohexa-3,5-dienone(32)

Under a stream of argon, 440 mg (11.0 mmol, 3.01 equivalents) of an oilydispersion of 60% sodium hydride was washed with hexane to remove theoil component. The dispersion kept cooled with cold water and 18.0 ml ofdry dimethyl sulfoxide added were stirred together. To the stirredsuspension, 900 mg (3.66 mmol) of phenyl-(2,3,4,6-tetrahydroxyphenyl)ketone (10) was added and stirred for 30 minutes. Further, 0.830 ml(7.32 mmol, 2.00 equivalents) of 1-chloro-3-methyl-2-butene was addeddropwise stirring for two hours. The produced mixture was combined with15 ml of a saturated aqueous ammonium chloride solution and 2 ml of 2 Mhydrochloric acid solution and extracted by ether. The organic layer waswashed with saturated brine, dried over sodium sulfate, concentratedunder a reduced pressure, and subjected to silica gel chromatography (gof Wako Gel C-200, eluted with hexane ethyl acetate 4:1) to obtain 716mg (yield 51.3%) of the product (32) in the form of yellow powderycrystals.

1H-NMR (90 HMz, CDCl₃) δ (TMS): 1.57-1.74 (12H, m), 2.63 (2H, d, J=7.5),3.10 (2H, d, J=7.5), 4.5 (1H, brs), 5.14 (2H, m), 7.23-7.7 (6H, m),18.65 (1H, s); 13C-NMR (90 MHz, CDCl₃) δ (TMS): 17.8, 18.1, 21.3, 25.7,25.9, 42.0, 79.1, 105.2, 109.4, 116.1, 121.1, 127.9, 128.1, 131.5,132.7, 136.9, 137.9, 168.8, 190.6, 193.5, 195, 2; LR-MS (EI, 70V, 300μA) 382 (M⁺), 314, 258, 229, 217, 180, 151, 105 (base), 77, 69.

Example 17

Synthesis of2,4-bisbenzyl-6-(3-methyl-1-oxobutyl)-2,3,5-trihydroxycyclohexa-3,5-dienone(33)

Under a stream of argon, 212 mg (5.31 mmol, 2.40 equivalents) of an oilydispersion of 60% sodium hydride was washed with hexane to remove theoil component. While the dispersion kept cooled with cold water, 11.0 mlof dry dimethyl sulfoxide was added and stirred. To this, was added 500mg (2.21 mmol) of 2-methylpropyl-(2,3,4,6-tetrahydroxyphenyl) ketone (9)and stirred for 40 minutes. To the produced mixture, 0.525 ml (4.42mmol, 2.00 equivalents) of benzyl bromide was added dropwise and stirredfor four hours. The resultant mixture was combined with 10 ml of asaturated aqueous ammonium chloride solution and extracted by ether. Theorganic layer was washed with saturated brine, dried over sodiumsulfate, concentrated under a reduced pressure, and subjected to silicagel chromatography (100 g of Wako Gel C-200, eluted with hexane:ethylacetate=3:2) to obtain 207 mg (yield 23.1%) of the product (33) in theform of yellow powdery crystals.

1H-NMR (90 MHz, CDCl₃) δ (TMS): 0.94 (6H, d, J=6.2), 2.25 (1H, m), 2-3(2H, br), 2.66 (2H, m), 3.04 (2H, s), 3.62 (2H, s), 7.1-7.4 (10H, m),18.3 (1H, brs); 13C-NMR (90 MHz, CDCl₃) δ (TMS): 22.7, 22.9, 25.7, 27.8,47.2, 50.5, 60.6, 105.6, 107.6, 125.9, 127.5, 128.0, 128.3, 128.8,130.4, 133.5, 140.7, 171.5, 189.2, 195.5, 200.3; LR-MS (E1, 70V, 300 μA)406 (M⁺), 322, 315 (base), 287, 259, 237, 209, 197, 181, 167, 91.

Example 18

Synthesis of {3,5-bisbenzyl-2,4,6-trihydroxyphenyl} (2-methylpropyl)ketone (34),2,2-bisbenzyl-6-(2-methyl-1-oxobutyl)-3,5-dihydroxycyclohexa-3,5-dienone(35), and2,2,4-trisbenzyl-6-(3-methyl-1-oxobutyl)-3,5-dihydroxycyclohexa-3,5-dienone(36)

Under a stream of argon, 738 mg (10.0 mmol, 2.00 equivalents) ofpotassium methoxide was dissolved in 25.0 ml of dry methanol coolingwith ice and stirred. To this was added 1.05 g (5.00 mmol) of2-methylpropyl-(2,4,6-trihydroxyphenyl) ketone (5) and stirred for onehour. Further, 1.19 ml (10.0 mmol, 2.00 equivalents) of benzyl bromidewas added dropwise and stirred for four hours cooling with ice. Theresultant mixture was combined with 10 ml of a saturated aqueousammonium chloride solution, distilled under a reduced pressure to removemethanol, and extracted by ether. The organic layer was washed withsaturated brine, dried over sodium sulfate, concentrated under a reducedpressure, and then subjected to silica gel chromatography (150 g of WakoGel C-200, eluted with hexane:diethyl ether at varyingratios=19:1-9:1-4:1) to produce sequentially by fractionation in theorder of elution2,2-bisbenzyl-6-(2-methyl-1-oxobutyl)-3,5-dihydroxycyclohexa-3,5-dienone(35),2,2,4-trisbenzyl-6-(3-methyl-1-oxobutyl)-3,5-dihydroxycyclohexa-3,5-dienone(36), and {3,5-bisbenzyl-2,4,6-trihydroxyphenyl)} (2-methylpropyl)ketone (34) in the respective amounts of 54.9 mg (yield 2.8%), 507 mg(yield 21.1%), and 150 mg (yield 7.7%) invariably in the form of yellowpowdery crystals.2,2-Bisbenzyl-6-(3-methyl-1-oxobutyl)-3,5-dihydroxycyclohexa-3,5-dienone(35)

1H-NMR (90 MHz, CDCl₃) δ (TMS): 0.93 (6H, d, J=6.6), 2.23 (1H, m), 2.91(2H, d, J=6.6), 3.99 (4H, s), 4.98, 5.53,5.98 (total 1H, s, brs, s),6.90-7.47 (10H, m), 9.86, 10.4, 18.82 (total 2H, brs, brs, s); LR-MS(EI, 70V, 300 μA) 390 (M⁺), 330 (base), 177, 91.

2,2,4-Trisbenzyl-6-(3-methyl-1-oxobutyl)-3,5-dihydroxycyclohexa-3,5-dienone(36)

1H-NMR (90 MHz, CDCl₃) δ (TMS): 0.78-1.04 (6H, m), 2.2 (1H, m),2.73-3.58 (8H, m), 5.6, 6.2 (total 1H, each brs), 6.85-7.25 (15H, m),18.68, 18.87 (total 1H, each s). LR-MS (EI, 70V, 300 μA) 480 (M⁺), 389,305, 91 (base).

3,5-Bisbenzyl-2,4,6-trihydroxyphenyl) (2-methylpropyl) ketone (34)

1H-NMR (90 MHz, CDCl₃) δ (TMS): 0.79-1.01 (6H, m), 1.5-2.4 (1H, m),2.59-2.93 (4H, m), 3.43-3.27 (4H, m), 6.93-7.25 (10H, m), 18.2-18.93(1H, m). LR-MS (E1, 70V, 30 μA) 390 (M⁺), 299 (base), 91.

Example 19

Synthesis of {3,5-bis(3-methylbutyl)-2,4,6-trihydroxyphenyl}(2-methylpropyl) ketone (37)

In 22.0 ml of ethanol, 1.50 g (4.34 mmol) of{3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (2-methylpropyl)ketone (15) was dissolved. The solution was stirred with 924 mg (0.217mmol, 5% equivalent) of 5% palladium carbon catalyst (water content upto 50%) under hydrogen atmosphere under ordinary pressure at roomtemperature for two hours. The solution was filtered and concentratedunder a reduced pressure to form a brown oil. This oil was subjected tosilica gel chromatography (using 100 g of Wako Gel C-200, eluted withhexane:ethyl acetate=10:1) to obtain 1.32 g (yield 86.6%) of the product(37) in the form of a colorless oily substance.

1H-NMR (400 MHz, CDCl₃) δ (TMS): 0.97 (18H, d, J=6.9), 1.37 (4H, m),1.64 (2H, m), 2.27 (1H, m), 2.54 (4H, m), 2.96 (2H, d, J=6.8), 4.58 (1H,s), 5.31 (1H, s), 9.69 (1H, brs); 13C-NMR (400 MHz, CDCl₃) δ (TMS):20.7, 22.5, 22.9, 25.2, 28.3, 38.2, 53.1, 105.1, 106.2, 157.5, 158.2,206.1; LR-MS (EI, 70V, 300 μA) 350 (M⁺), 293 (base), 279, 275.

Referential Example 7

Synthesis of (phenylmethyl) (2,4,6-trihydroxyphenyl) ketone (38)

In a solvent mixture of 45 ml of nitrobenzene and 45 ml of carbondisulfide, 12.61 g (100.0 mmol) of fluoroglucinol was added and stirredcooling with cold water. To this, 40.0 g (300 mmol, 3.00 equivalents) ofaluminum chloride was added piecemeal with stirring, attached with acalcium chloride tube. To the resultant mixture, 15.46 g (100.0 mmol,1.000 equivalent) of phenyl acetyl chloride slowly was added dropwiseand stirred at room temperature for two hours. When the evolution of anacidic gas ceased, the solution was poured into dilute hydrochloric acid(prepared from 100 ml of concentrated hydrochloric acid and 400 ml ofcold water) with stirring, and then extracted by ether. The ether layerwas washed with saturated brine and removed ether under a reducedpressure. The residue was combined with water and distilled under areduced pressure, subjected to steam distillation to removenitrobenzene. The residue was again extracted by ether, washed withsaturated brine, dried over sodium sulfate, and distilled to remove thesolvent and obtain 26.02 g of a red viscous oily substance. The oilysubstance was combined with a small amount of methylene chloride andleft standing until crystallization in a refrigerator to obtain 19.62 gof (phenylmethyl) (2,4,6-trihydroxyphenyl) ketone (38) in the form oflight yellow powdery crystals.

(38) 1H-NMR (CDCl₃): 4.42 (2H, s), 5.93 (2H, s), 7.19-7.34 (5H, m).

Example 20

Synthesis of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl}(phenylmethyl) ketone (39),3,5-dihydroxy-6-(phenylacetyl)-2,2,4-tris(3-methyl-2-butenyl)-cyclohexa-3,5-dienone(40),3,5-dihydroxy-6-(phenylacetyl)-2,2-bis(3-methyl-2-butenyl)cyclohexa-3,5-dienone(41), and {3-(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (phenylmethyl)ketone (42)

Under an atmosphere of nitrogen, a dry methanol (3.0 ml) solution of 733mg (3.00 mmol) of (phenylmethyl) (2,4,6-trihydroxyphenyl) ketone (38)was added cooling with ice and stirred to a dry methanol (6.0 ml)solution of 324 mg (6.00 mmol, 2.00 equivalents) of sodium methoxide. Tothe solution, a methanol (4.0 ml) solution of 627 mg (6.00 mmol, 2.00equivalents) of 1-chloro-3-methyl-2-butene was slowly added. Theresultant mixture was stirred for three hours. The mixture was distilledunder a reduced pressure at room temperature to remove methanol and thencombined with ether. The ether layer was washed with saturated brine,dried over sodium sulfate, and distilled to remove the solvent andobtain 1.027 g of a crude product. This crude product was subjected tosilica gel column chromatography (46 g of Wako Gel C-300, eluted withhexane:ether at varying ratios=19:1-1:1) to produce sequentially byfractionation in the order of elution 13 mg of{3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (phenylmethyl)ketone (39) in the form of a yellow viscous oily substance, 98 mg of3,5-dihydroxy-6-(phenylacetyl)-2,2,4-tris(3-methyl-2-butenyl)cyclohexa-3,5-dienone(40) in the form of a yellow viscous oily substance, 136 mg of3,5-dihydroxy-6-(phenylacetyl)-2,2-bis(3-methyl-2-butenyl)cyclohexa-3,5-dienone(41) in the form of a yellow solid, and 165 mg of{3-(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (phenylmethyl) ketone(42) in the form of yellow crystals.

(39) 1H-NMR (CDCl₃): 1.79 (6H, d, J=1.2), 1.84 (6H, s), 3.37 (2H, d,J=7.3), 4.41 (2H, s), 5.22 (1H, m), 7.29 (5H, m); (40) 1H-NMR (CDCl₃):(major isomer) 1.54 (6H, s), 1.56 (6H, s), 1.77 (6H, s), 2.53 (2H, d,J=7.8), 2.64 (2H, d, J=7.3), 3.17 (2H, d, J=7.3), 4.74 (2H, m), 5.12(1H, m), 7.29 (5H, m); (minor isomer) 1.54 (6H, s), 1.56 (6H, s), 1.77(6H, s), 2.67 (2H, d, J=7.3), 3.21 (2H, d, J=7.3), 4.74 (2H, m), 5.12(1H, m), 7.29 (5H, m); (41) 1H-NMR (CDCl₃): 1.52 (3H, s), 1.55 (3H, s),1.56 (6H, s), 2.73 (4H, m), 4.41 (2H, s), 4.80 (1H, m); (42) 1H-NMR(CDCl₃): 1.68 (3H, s), 1.76 (3H, s), 3.26 (2H, d, J=7.0), 4.41 (2H, s),6.00 (1H, s), 7.18-7.33 (5H, m).

Example 21

Synthesis of{3,5-bis(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl}(phenylmethyl) ketone (43),3,5-dihydroxy-6-(phenylacetyl)-2,2,4-tris(3,7-dimethyl-2,6-octadienyl)cyclohexa-3,5-dienone(44),3,5-dihydroxy-6-(phenylacetyl)-2,2-bis(3,7-dimethyl-2,6-octadienyl)cyclohexa-3,5-dienone(45), and {3-(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl}(phenylmethyl) ketone (46)

Under an atmosphere of nitrogen, a dry methanol (3.0 ml) solution of 733mg (3.00 mmol) of (phenylmethyl) (2,4,6-trihydroxyphenyl) ketone (38)was added while stirred at room temperature to a dry methanol (6.0 ml)solution of 324 mg (6.00 nmol, 2.00 equivalents) of sodium methoxide.Further, a methanol (5.0 ml) solution of 1.036 g (6.00 mmol, 2.00equivalents) of 1-chloro-3,7-dimethyl-2,6-octadiene was slowly added.They were stirred at room temperature for three hours and then at 60° C.for one hour. The produced mixture was distilled under a reducedpressure at room temperature to remove methanol and then combined withether. The ether layer was washed with saturated brine, dried oversodium sulfate, and then distilled off the solvent and obtain 1.567 g ofa crude product. This crude product was subjected to silica gel columnchromatography (50 g of Wako Gel C-300, eluted with hexane:ether atvarying ratios=19:1-6:1) to produce sequentially by fractionation in theorder of elution 132 mg of{3,5-bis(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl}(phenylmethyl) ketone (43) in the form of an orange viscous oilysubstance, 166 mg of3,5-dihydroxy-6-(phenylacetyl)-2,2,4-tris(3,7-dimethyl-2,6-octadienyl)cyclohexa-3,5-dienone(44) in the form of a yellow viscous oily substance, 203 mg of3,5-dihydroxy-6-(phenylacetyl)-2,2-bis(3,7-dimethyl-2,6-octadienyl)cyclohexa-3,5-dienone(45) in the form of an orange viscous oily substance, and 222 mg of{3-(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl} (phenylmethyl)ketone (46) in the form of yellow crystals.

(43) 1H-NMR (CDCl₃): 1.59 (6H, s), 1.69 (12H, s), 1.97 (8H, m), 4.23(2H, s), 5.05 (4H, m), 7.29 (5H, m); (44) 1H-NMR (CDCl₃): 1.54 (15H, s),1.60 (3H, s), 1.64 (3H, s), 1.65 (3H, s), 1.69 (3H, s), 1.75-2.20 (4H,m), 3.20 (2H, d), 4.39 (2H, s), 4.79 (2H, m), 4.98 (2H, m), 5.04 (1H,m), 5.24 (1H, m), 7.29 (5H, m); (45) 1H-NMR (CDCl₃): 1.55 (9H, s), 1.65(3H, s), 1.88 (8H, m), 2.63 (4H, m), 4.40 (2H, s), 4.85 (2H, m), 4.94(2H, m), 7.28 (5H, m); (46) 1H-NMR (CDCl₃): 1.57 (3H, s), 1.65 (3H, s),1.77 (3H, s), 2.00 (4H, m), 3.29 (2H, d, J=6.8), 4.41 (2H, s), 5.09 (1H,m), 5.24 (1H, m), 7.25 (5H, m).

Referential Example 8

Synthesis of (2,4-dihydroxy-6-methylphenyl) (2-methylpropyl) ketone (47)

Orcinol monohydride, 14.20 g (100.0 mmol), in 160 ml of benzene washeated to distill benzene. This step was carried out twice by way of anoperation of dehydration. The product of dehydration was dissolved in 45ml of nitrobenzene and 45 ml of carbon disulfide, and 26.7 g (200 mmol,2.00 equivalents) of aluminum chloride was added piecemeal while cooledwith cold water and stirred, with a calcium chloride tube attached.Then, 12.1 g (100 mmol, 1.00 equivalent) of isovaleryl chloride wasslowly added dropwise and stirred at room temperature for 14 hours.After the stop of the evolution of an acidic gas was confirmed, theresultant reaction mixture was poured into dilute hydrochloric acid(prepared from 100 ml of concentrated hydrochloric acid and 400 ml ofcold water), stirred, and then extracted by ether. The ether layer waswashed with saturated brine and the ether was removed under a reducedpressure. The residue was combined with water added piecemeal andmeanwhile distilled under a reduced pressure to remove nitrobenzene bysteam distillation. The residue was extracted by ether, washed withsaturated brine, dried over sodium sulfate, and distilled off thesolvent and obtain 18.53 g of a crude product in the form of brownviscous oily substance. The crude product was subjected to silica gelcolumn chromatography (220 g of Wako Gel C-200, eluted with hexane:ethylacetate=9:1) to obtain 5.681 g of (2,4-dihydroxy-6-methylphenyl)(2-methylpropyl) ketone (47).

(47) 1H-NMR (CDCl₃): 0.97 (6H, d, J=6.5), 2.25 (3H, s), 2.27 (1H, m),2.78 (2H, d, J=6.6), 6.23 (1H, s), 6.26 (1H, s).

Example 22

Synthesis of {2-hydroxy-6-methyl-4-(3-methyl-2-butenyloxy)phenyl}(2-methylpropyl) ketone (48),{2,4-dihydroxy-6-methyl-3-(3-methyl-2-butenyl)phenyl} (2-methylpropyl)ketone (49), and {4,6-dihydroxy-2-methyl-3-(3-methyl-2-butenyl)phenyl}(3-methylpropyl) ketone (50)

Under an atmosphere of nitrogen, 300 mg (7.50 mmol, 1.50 equivalents) ofan oil dispersion of 60% sodium hydride was washed with petroleum etherto remove paraffin and then combined with 7.5 ml of dry methanol. Then,a methanol (5.0 ml) solution of 1.04 g (5.00 mmol) of(2,4-dihydroxy-6-methylphenyl) (2-methylpropyl) ketone (47) was addedcooling with ice and stirred. Further, a methanol (5.0 ml) solution of784 mg (7.50 mmol, 1.50 equivalents) of 1-chloro-3-methyl-2-butene wasslowly added dropwise. The resultant mixture was stirred at roomtemperature for two hours. The mixture was combined with ether. Theether layer was washed with a saturated aqueous ammonium chloridesolution and saturated brine, dried over sodium sulfate, and distilledto remove the solvent and obtain 1.296 g of a dark red oily substance.This oily substance was combined with a small amount of hexane and leftstanding in a refrigerator to recover 277 mg of the starting substancein the form of colorless needle crystals. The filtrate, 965 mg inweight, was subjected to silica gel column chromatography (49 g of WakoGel C-300, eluted with hexane:ethyl acetate at varying ratios=29 1-7:3)to produce sequentially by fractionation in the order of elution 108 mgof {2-hydroxy-6-methyl-4-(3-methyl-2-butenyloxy)phenyl} (2-methylpropyl)ketone (48) in the form of a yellow oily substance, 78 mg of{2,4-dihydroxy-6-methyl-3-(3-methyl-2-butenyl) phenyl} (2-methylpropyl)ketone (49) in the form of colorless fine crystals, and 260 mg of ayellowish brown oily substance which was again purified by columnchromatography (6.0 g of Wako Gel C-300, eluted with hexane:ethylacetate=19:1) to obtain 162 mg of{4,6-dihydroxy-2-methyl-3-(3-methyl-2-butenyl)phenyl} (3-methylpropyl)ketone (50) in the form of a yellow viscous oily substance.

(48) 1H-NMR (CDCl₃): 0.97 (6H, d, J=6.6), 1.74 (3H, s), 1.79 (3H, s),2.22 (1H, m), 2.55 (3H, s), 2.78 (2H, d, J=6.8), 4.51 (2H, d, J=6.8),5.46 (1H, m), 6.30 (1H, s); (49) 1H-NMR (CDCl₃): 0.96 (6H, d, J=6.4),1.74 (3H, s), 1.80 (3H, s), 2.28 (1H, m), 2.51 (3H, s), 2.77 (2H, d,J=6.6), 3.40 (2H, d, J=6.7), 5.27 (1H, m), 6.20 (1H, s); (50) 1H-NMR(CDCl₃): 0.92 (6H, d, J=6.6), 1.73 (3H, s), 1.79 (3H, s), 2.28 (1H, m),2.41 (3H, s), 2.74 (2H, d, J=6.6), 3.31 (2H, d, J=6.6), 5.07 (1H, m),6.26 (1H, s).

Example 23

Synthesis of{3,5-bis(3-methyl-2-butenyl)-2-hydroxy-6-methyl-4-(3-methyl-2-butenyloxy)phenyl}(2-methylpropyl) ketone (51), and{2,4-dihydroxy-6-methyl-3-(3-methyl-2-butenyl)phenyl} (2-methylpropyl)ketone (49)

To a solution of 1.04 g (5.00 mmol) of (2,4-dihydroxy-6-methylphenyl)(2-methylpropyl) ketone (47) in dry 1,4-dioxane (10.0 ml), undernitrogen atmosphere, added 710 mg (5.00 mmol, 1.00 equivalent) of borontrifluoride ether complex in dioxane (5.0 ml) at 10° C. with stirring.Then, added 861 mg (10.0 mmol, 2.00 equivalents) of 3-methyl-2-butenolin dioxane (5.0 ml) slowly, allowing to elevate to room temperature, andstirred for five hours. Added ether to the reaction mixture and washedthe ether layer with saturated sodium hydrogen carbonate aqueoussolution and saturated brine, and dried over sodium sulfate. By removalof the solvent, obtained orange-colored oily substance as a crudeproduct. Column chromatographic separation on silica gel (65 g of WakoGel C-300, eluted with hexane: ethyl acetate at varying ratios=19:1-7:3)gave, in the order of elution, 246 mg of{3,5-bis(3-methyl-2-butenyl)-2-hydroxy-6-methyl-4-(3-methyl-2-butenyloxy)phenyl}(2-methylpropyl)ketone (51) as a light yellow viscous oil and 95 mg of{2,4-dihydroxy-6-methyl-3-(3-methyl-2-butenyl)phenyl}(2-methylpropyl)ketone (49) as a light yellow fine needles.

(51) 1H-NMR (CDCl₃): 0.92 (6H, d, J=6.4), 1.74 (18H, m), 2.18 (1H, m),2.38 (3H, s), 2.73 (2H, d, J=7.2), 3.31 (2H, d, J=8.4), 3.41 (2H, d,J=8.6), 3.94 (2H, d, J=6.8), 5.06 (2H, m), 5.37 (2H, m).

Referential Example 9

Synthesis of (2,4-dihydroxyphenyl)(2-methylpropyl) ketone (52)

Resorcinol, 5.506 g (50.00 mmol), was added to 45 ml of nitrobenzene andstirred cooling with cold water and 13.3 g (100 mmol, 2.00 equivalents)of aluminum chloride was added piecemeal and they were stirred, with acalcium chloride tube attached. Then, 6.03 g (50.0 mmol, 1.00equivalent) of isovaleryl chloride was slowly added dropwise, stirred atroom temperature for one hour, and further heated stirring at 90° C. forsix hours. When the evolution of an acidic gas ceased, the resultantmixture was poured into dilute hydrochloric acid (prepared from 40 ml ofconcentrated hydrochloric acid and 160 ml of cold water) with stirring,and then extracted by ether. The ether layer was washed with saturatedbrine and removed by distillation under a reduced pressure. The residue,with water added piecemeal, was distilled under a reduced pressure anddistilled off nitrobenzene by steam distillation method. The residue wasextracted again by ether, washed with saturated brine, dried over sodiumsulfate, and distilled to remove the solvent and obtain 8.952 g of a redviscous oily substance. This oily substance was purified by silica gelcolumn chromatography (20 g of Wako Gel C-200, eluted with hexane:etherat varying ratios=8:2-7:3) to obtain 4.37 g of (2,4-dihydroxyphenyl)(2-methylpropyl) ketone (52) in the form of light yellow crystals.

Example 24

Synthesis of {2-hydroxy-4-(3-methyl-2-butenyloxy) phenyl}(2-methylpropyl) ketone (53) and(2,4-dihydroxy-3-(3-methyl-2-butenyl)phenyl) (2-methylpropyl) ketone(54)

Under an atmosphere of nitrogen, 486 mg (2.50 mmol) of(2,4-dihydroxyphenyl) (2-methylpropyl) ketone (52) and 784 mg (7.50mmol, 3.00 equivalents) of 1-chloro-3-methyl-2-butene were dissolved in7.0 ml of dry methanol. To the solution which was stirred at roomtemperature, a methanol (7.5 ml) solution of 405 mg (7.50 mmol, 3.00equivalents) of sodium methoxide was slowly added dropwise. Theresultant mixture was stirred at room temperature for three hours andthen at 50° C. for one hour, and distilled at room temperature under areduced pressure to remove methanol, and combined with ether. The etherlayer was washed with a saturated aqueous ammonium chloride solution andsaturated brine, dried over sodium sulfate, distilled off the solventand obtain 661 mg of a red oily substance. The crude product wassubjected to silica gel column chromatography (20 g of Wako Gel C-300,eluted with hexane:ether at varying ratios=50:1-4:1) to producesequentially by fractionation in the order of elution 139 mg of{2-hydroxy-4-(3-methyl-2-butenyloxy)phenyl} (2-methylpropyl) ketone (53)in the form of a colorless oily substance and 41 mg of{2,4-dihydroxy-3-(3-methyl-2-butenyl)phenyl} (2-methylpropyl) ketone(54) in the form of colorless crystals.

(53) 1H-NMR (CDCl₃): 1.00 (6H, d, J=6.4), 1.75 (3H, s), 1.79 (3H, s),2.26 (1H, m), 2.75 (2H, d, J=6.6), 4.53 (2H, d, J=6.8), 5.46 (1H, m),6.42 (1H, d, J=2.4), 6.43 (1H, dd, J=9.6, 2.4), 7.64 (1H, d, J=9.6);(54) 1H-NMR (CDCl₃): 1.00 (6H, d, J=6.4), 1.76 (3H, s), 1.83 (3H, s),2.26 (1H, m), 2.75 (2H, d, J=7.0), 3.44 (2H, d, J=7.0), 5.27 (1H, m),6.36 (1H, d, J=8.8), 7.55 (1H, d, J=8.8).

Example 25

Synthesis of {2,4-dihydroxy-5-(3-methyl-2-butenyl) phenyl}(2-methylpropyl) ketone (55)

Under an atmosphere of nitrogen, 355 mg (2.50 mmol, 1.00 equivalent) ofboron trifluoride ether complex was added at 10° C. to a dry 1,4-dioxane(5.0 ml) solution of 486 mg (2.50 mmol) of (2,4-dihydroxyphenyl)(2-methylpropyl) ketone (52). Then, a dioxane (2.0 ml) solution of 431mg (5.00 mmol, 2.00 equivalents) of 3-methyl-2-butenol was slowly addeddropwise and stirred at room temperature for 22 hours and then at 50° C.for three hours. The reaction mixture was combined with ether. The etherlayer was washed with a saturated aqueous sodium hydrogen carbonatesolution and saturated brine and dried over sodium sulfate.

The reaction mixture was distilled off the solvent and obtain 864 mg ofa colorless oily substance. The crude product was subjected to silicagel column chromatography (25 g of Wako Gel C-300, eluted withhexane:ether at varying ratios=19:1-4:1) to obtain 136 mg of(2,4-dihydroxy-5-(3-methyl-2-butenyl) phenyl) (2-methylpropyl) ketone(55).

(55) 1H-NMR (CDCl₃): 1.01 (6H, d, J=6.6), 1.79 (6H, s), 2.26 (1H, m),2.75 (2H, d, J=6.6), 3.30 (2H, d, J=8.3), 5.30 (1H, m), 6.36 (1H, s),7.45 (1H, s).

Example 26

(1) Preparation of Cells

ICR mice 11-12 days old (purchased from Charles River Japan) wereeuthanized by anesthesia with ether and immediately immersed in 70%ethanol for disinfection. By the use of ophthalmologist scissors andpincers sterilized in advance with ethanol, femur and tibia were excisedfrom the sacrificed mice and chopped into small pieces in an α-MEMculture medium (purchased from Flow Laboratories Corp.). containing 5%FBS (purchased from Irvine Scientific Corp.), 100 U/ml penicillin and100 μg/ml streptomycin. The supernatant formed consequently wasrecovered by pipeting, cleaned with the culture broth, and suspended ina 5% FBS α-MEM culture broth to obtain bone cells containing osteoclastcells. The supernatant of a bone cell-floating liquid formed after 3minutes' standing of the bone cells at rest was recovered and passedthrough a mesh (cell strainer, 70 μm, purchased from Falcon Corp.). Thefiltrate was adjusted to a cell concentration of 1×10⁷/ml and used forthe pit formation assay.

(2) Test by Pit Formation Assay

An ivory piece was cut into slices, 150 μm in thickness, by the use of aprecision low-speed cutting machine (purchased from Buehler Corp.).Cylindrical holes, 6 mm in diameter, were perforated in the slices bythe use of a one-hole punch. The ivory slices were immersed in 70%ethanol and subjected therein to an ultrasonic cleaning treatment twiceeach for five minutes and washed three times with a sterilized PBS andtwice with the culture medium. The ivory slices were set in place on a96-hole culture plate (purchased from Falcon Corp.). The perforatedivory slices on the culture plate, with a culture broth containing agiven compound of the present invention prepared in a concentration of2×10⁻⁵ M added in a fixed volume of 100 μl (final medicine concentration1×10⁻⁵ M) to each of the holes and a culture broth containing preparedbone cells in a concentration of 1×10⁷/ml placed in each of the holes,were cultured for three days in a 10% CO₂ incubator at 37° C. After theculture, the ivory slices were placed in an aqueous 2 N sodium hydroxideand the cells on the slices were removed by the use of a rubber spatula.The ivory slices were washed with water and methanol. The absorptionpits formed in the ivory slices were dyed with Coomassie Brilliant Blueand were counted under a microscope. Though the numbers of absorptionpits were naturally found to disperse among test lots, depending on theratios of varying specie s of cells in the bone cell suspensions and thelots of animals used, satisfactorily uniform test results were found inone and the same test lot. The ratio of inhibition of osteolysis wascalculated on the 100% scale, in which 0% stands for the number ofabsorption pits found in the culture broth in the presence of rPTH(1×10⁻⁸ M) and in the absence of a medicine and 100% for total absenceof absorption pit.

The test described above was performed in a total of ten runs, Tests1-10. The results are shown in Table 2 and Table 3. It is clearly notedfrom the results that the compounds of the present invention exhibitedprominently high ratios of inhibition of osteolysis and, therefore, wereuseful as substances possessing an activity to repress osteolysis.

In the columns titled “Added medicine No.” found in Table 2 and Table 3,the symbol (-) denotes a control involving no addition of medicine andthe numerical No. denotes the No. of the compound mentioned above.

TABLE 2 Concentration No. of Compound No. of compound absorption pitsRatio of added (M) (Mean ± SD) inhibition (%) Test 1 (−) 0 80.1 ± 5.6 013 10⁻⁵ M 16.8 ± 3.6 79.0 14 10⁻⁵ M 26.0 ± 2.6 67.5 15 10⁻⁵ M  8.3 ± 2.489.6 16 10⁻⁵ M 0 100.0 Test 2 (−) 0 201.8 ± 10.9 0 25  0⁻⁵ M 0 100.0 2610⁻⁵ M 29.3 ± 4.8 85.5 27 10⁻⁵ M 38.8 ± 6.6 80.8 28 10⁻⁵ M 61.3 ± 5.569.6 33 10⁻⁵ M  9.8 ± 1.8 95.1 Test 3 (−) 0 98.9 ± 9.3 0 29 10⁻⁵ M 20.3± 2.1 79.5 30 10⁻⁵ M 21.4 ± 3.9 78.2 32 10⁻⁵ M 33.9 ± 4.1 65.7 Test 4(−) 0 162.6 ± 17.8 0 24 10⁻⁵ M  39.3 ± 13.9 75.8 37 10⁻⁵ M 14.4 ± 4.991.1 Test 5 (−) 0 187.7 ± 21.0 0  6 10⁻⁵ M  63.4 ± 12.4 61.4 19 10⁻⁵ M55.3 ± 6.1 70.5 20 10⁻⁵ M  3.0 ± 1.3 98.4 21 10⁻⁵ M  3.5 ± 1.4 98.1 2210⁻⁵ M  3.5 ± 1.1 98.1

TABLE 3 Concentration No. of Compound No. of compound absorption pitsRatio of added (M) (Mean ± SD) inhibition (%) Test 6 (−) 0 201.8 ± 20.20 34 10⁻⁵ M  8.2 ± 1.9 95.9 36 10⁻⁵ M  3.8 ± 0.9 98.1 47 10⁻⁵ M 179.8 ±23.8 10.9 48 10⁻⁵ M 85.2 ± 7.5 57.8 49 10⁻⁵ M 44.3 ± 5.4 78.0 50 10⁻⁵ M40.1 ± 7.0 80.1 51 10⁻⁵ M 102.7 ± 6.2  42.8 Test 7 (−) 0 179.6 ± 34.4 039 10⁻⁵ M 49.2 ± 9.4 72.6 Test 8 (−) 0 125.3 ± 12.2 0 38 10⁻⁵ M 55.8 ±7.7 57.9 40 10⁻⁵ M  4.9 ± 3.8 96.1 41 10⁻⁵ M  3.2 ± 0.7 97.4 42 10⁻⁵ M31.7 ± 3.6 74.7 Test 9 (−) 0 224.8 ± 20.0 0 43 10⁻⁵ M 11.3 ± 2.5 95.0 4410⁻⁵ M  7.7 ± 2.0 96.6 45 10⁻⁵ M  8.2 ± 1.8 96.4 46 10⁻⁵ M 125.3 ± 12.644.3 Test 10 (−) 0 171.2 ± 16.6 0 52 10⁻⁵ M  94.3 ± 13.8 44.9 53 10⁻⁵ M 55.1 ± 11.1 67.8 54 10⁻⁵ M 66.5 ± 9.7 61.2 55 10⁻⁵ M 15.8 ± 3.3 90.8

Translation of Annexes

Accompanying Internatinal Preliminary Examination Report

What we claim is:
 1. A member of the group consisting of a compound ofthe formula

wherein R₁ is 2-methylpropyl or 2,6-dimethylheptyl and R₂ and R₃ areindividually selected from the group consisting of hydrogen,3-methyl-2-butenyl, 3,7-dimethyl-2,6-octadienyl and benzyl unsubstitutedor substituted with at least one member of the group consisting ofhalogen, —OH, alkoxy of 1 to 15 carbon atoms, alkenyloxy of 2 to 15carbon atoms and acyl of an organic carboxylic acid, providing that whenR₁ is 2-methylpropyl, R₂ and R₃ are not hydrogen or 3-methyl-2-butenyl.2. A compound of claim 1 wherein R₂ and R₃ are individually selectedfrom the group consisting of hydrogen, 3-methyl-2-butenyl,3,7-dimethyl-2,6-octadienyl and benzyl.
 3. A member of the groupconsisting of a compound of the formula

wherein R₁ is selected from the group consisting of alkyl of 1 to 15carbon atoms, benzyl unsubstituted or substituted with at least onemember of the group consisting of halogen, —OH, alkoxy of 1 to 15 carbonatoms, alkenyloxy of 2 to 15 carbon atoms and acyl of an organiccarboxylic acid and optionally substituted aryl, R₂ and R₄ areindividually selected from the group consisting of hydrogen, alkyl of 1to 15 carbon atoms, alkenyl of 2 to 15 carbon atoms and optionallysubstituted benzyl, and R₅, R₆ and R₇ are individually selected from thegroup consisting of hydrogen, alkyl of 1 to 15 carbon atoms, alkenyl of2 to 15 carbon atoms and benzyl unsubstituted or substituted with atleast one member of the group consisting of halogen, —OH, alkoxy of 1 to15 carbon atoms, alkenyloxy of 2 to 15 carbon atoms and acyl of anorganic carboxylic acid or a salt thereof with a non-toxic,pharmaceutically acceptable base.
 4. A compound of claim 3 wherein R₁ isselected from the group consisting of 2-methylpropyl,2,6-dimethylheptyl, benzyl, and phenyl or a salt thereof.
 5. A compoundselected from the group consisting of{3,5-bisbenzyl-2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone,{3,5-bis(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl}(2-methylpropyl) ketone, {3-(3-methyl-2-butenyl)-2,4,5-trihydroxyphenyl}(2-methylpropyl) ketone,{3,6-bis(3-methyl-2-butenyl)-2,4,5-trihydroxyphenyl} (2-methylpropyl)ketone, {6-(3-methyl-2-butenyl)-2,4,5-trihydroxyphenyl} (2-methylpropyl)ketone mono(3-methyl-2-butenyl) ether, (2,4,5-trihydroxyphenyl)(2-methylpropyl) ketone mono(3-methyl-2-butenyl) ether,{3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (plenylmethyl)ketone, {3-(3-methyl 2-butenyl)-2,4,6-trihydroxyphenyl} (phenylmethyl)ketone, {3,5-bis(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl}(phenylmethyl) ketone,{3-(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxyphenyl} (phenylmethyl)ketone, {2-hydroxy-6-methyl-4-(3-methyl-2-butenyloxy)phenyl}(2-methylpropyl) ketone,{2,4-dihydroxy-6-methyl-3-(3-methyl-2-butenyl)phenyl} (2-methylpropyl)ketone, {4,6-dihydroxy-2-methyl-3-(3-methyl-2-butenyl)phenyl}(3-methylpropyl) ketone,{3,5-bis(3-methyl-2-butenyl)-2-hydroxy-6-methyl-4-(3-methyl-2-butenyloxy)phenyl}(2-methylpropyl) ketone. {2-hydroxy-4-(3-methyl-2-butenyloxy)phenyl}(2-methylpropyl) ketone, {2,4-dihydroxy-3-(3-methyl-2-butenyl)phenyl}(2-methylpropyl) ketone, and{2,4-dihydroxy-5-(3-methyl-2-butenyl)phenyl} (2-methylpropyl) ketone anda salt thereof.
 6. A compound of the formula

wherein R₁ is selected from the group consisting of alkyl of 1 to 15carbon atoms, benzyl unsubstituted or substituted with at least onemember of the group consisting of halogen, —OH, alkoxy of 1 to 15 carbonatoms, alkenyloxy of 2 to 15 carbon atoms and acyl of an organiccarboxylic acid, and aryl unsubstituted or substituted with at least onemember of the group consisting of halogen, —OH, alkoxy of 1 to 15 carbonatoms, alkenyloxy of 2 to 15 carbon atoms and acyl of an organiccarboxylic acid, R₂ is selected from the group consisting of hydrogen,alkyl of 1 to 15 carbon atoms, alkenyl of 2 to 15 carbon atoms, andoptionally substituted benzyl, R₃ is selected from the group consistingof alkyl of 1 to 15 carbon atoms, alkenyl of 2 to 15 carbon atoms andbenzyl unsubstituted or substituted with at least one member of thegroup consisting of halogen, —OH, alkoxy of 1 to 15 carbon atoms,alkenyloxy of 2 to 15 carbon atoms and acyl of an organic carboxylicacid, and R₈ is selected from the group consisting of hydroxyl, alkyl of1 to 15 carbon atoms, alkenyl of 2 to 15 carbon atoms, and benzylunsubstituted or substituted with at least one member of the groupconsisting of halogen, —OH, alkoxy of 1 to 15 carbon atoms, alkenyloxyof 2 to 15 carbon atoms and acyl of an organic carboxylic acid, with theproviso that when R₂ and R₃ are each 3-methyl-2-butenyl, R₁ is methyland R₈ is hydroxyl and when two or three members of the class consistingof R₂, R₃, and R₈ are each 3-methyl-2-butenyl, the remaining member isnot hydrogen or hydroxyl when R₁ is 2-propyl, 2-methylpropyl or1-methylpropyl and a salt thereof with a non-toxic, pharmaceuticallyacceptable base.
 7. A compound of claim 6 wherein R₁ is 2-methylpropyl,2,6-dimethylheptyl, or phenyl and a salt thereof.
 8. A compound of claim6 wherein R₂ or R₃ are 3-methyl-2-butenyl, 3,7-dimethyl-2,6-octadienyl,or benzyl and a salt thereof.
 9. A compound of claim 6 having theformula

wherein R₁ is 2-methylpropyl or 2,6-dimethylheptyl, R₂ is selected fromthe group consisting of hydrogen, 3-methyl-2-butenyl,3,7-dimethyl-2,6-octadienyl and benzyl unsubstituted or substituted withat least one member of the group consisting of halogen, —OH, alkoxy of 1to 15 carbon atoms, alkenyloxy of 2 to 15 carbon atoms and acyl of anorganic carboxylic acid, and R₃ is selected from the group consisting of3-methyl-2-butenyl, 3,7-dimethyl-2,6-octadienyl and benzyl unsubstitutedor substituted with at least one member of the group consisting ofhalogen, —OH, alkoxy of 1 to 15 carbon atoms, alkenyloxy of 2 to 15carbon atoms and acyl of an organic carboxylic acid, providing that whenR₁ is 2-methylpropyl or 2-propyl, R₂ is hydrogen or 3-methyl-2-butenyl,R₃ is not 3-methyl-2-butenyl and a salt thereof.
 10. A compound of claim6 having the formula

wherein R₁ is selected from the group consisting of 2-methylpropyl andaryl unsubstituted or substituted with at least one member of the groupconsisting of halogen, —OH, alkoxy of 1 to 15 carbon atoms, alkenyloxyof 2 to 15 carbon atoms and acyl of an organic carboxylic acid and R₂and R₃ are individually 3-methyl-2-butenyl or benzyl unsubstituted orsubstituted with at least one member of the group consisting of halogen,—OH, alkoxy of 1 to 15 carbon atoms, alkenyloxy of 2 to 15 carbon atomsand acyl of an organic carboxylic acid, providing that when R₁ is2-methylpropyl, R₂ and R₃ are not each 3-methyl-2-butenyl and a saltthereof with a non-toxic, pharmaceutically acceptable base.
 11. Acompound of claim 6 selected from the group consisting of2,2-bis(3,7-dimethyl-2,6-octadienyl)-3,5-dihydroxy-6-(3-methyl-1-oxobutyl)cyclohexa-3,5-dienone,3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-2,2,4-tris(3,7-dimethyl-2,6-octadienyl)cyclohexa-3,5-dienone,2,2-bisbenzyl-3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-cyclohexa-3,5-dienone,3,5-dihydroxy-6-(3-methyl-1-oxobutyl)-2,2,4-trisbenzylcyclohexa-3,5-dienone,2,2-bis(3-methyl-2-butenyl)-3,5-dihydroxy-6-(3,7-dimethyl-1-oxooctyl)cyclohexa-3,5-dienone,3,5-dihydroxy-6-(3,7-dimethyl-1-oxooctyl)-2,2,4-tris(3-methyl-2-butenyl)cyclohexa-3,5-dienone,2,4-bis(3-methyl-2-butenyl)-6-(benzoyl)-2,3,5-trihydroxycyclohexa-3,5-dienone,2,4-dimethyl-6-(3-methyl-1-oxobutyl)-2,3,5-trihydroxycyclohexa-3,5-dienone,2,4-bisbenzyl-6-(3-methyl-1-oxobutyl)-2,3,5-trihydroxycyclohexa-3,5-dienone,3,5-dihydroxy-6-(phenylacetyl)-2,2,4-tris(3-methyl-2-butenyl)cyclohexa-3,5-dienone,3,5-dihydroxy-6-(phenylacetyl)-2,2-bis(3-methyl-2-butenyl)cyclohexa-3,5-dienone,3,5-dihydroxy-6-(phenylacetyl)-2,2,4-tris(3,7-dimethyl-2,6-octadienyl)cyclohexa-3,5-dienone,3,5-dihydroxy-6-(phenylacetyl)-2,2-bis(3,7-dimethyl-2,6-octadienyl)cyclohexa-3,5-dienoneor a salt thereof.
 12. A composition for treating bones and cartilagecomprising an effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.
 13. A composition of claim 12 whichis a curative agent for diseases affecting bones and cartilages.
 14. Amethod for treating diseases of bones-cartilages in warm-blooded animalscomprising administering to warm-blooded animals a compound of claim 1in an amount effective in treating or preventing diseases ofbones-cartilages.
 15. A composition useful as a curative agent fordiseases affecting bones-cartilages, comprising an effective amount of acompound of the formula

wherein R₁ is selected from the group consisting of alkyl of 1 to 15carbon atoms, benzyl unsubstituted or substituted with at least onemember of the group consisting of halogen, —OH, alkoxy of 1 to 15 carbonatoms, alkenyloxy of 2 to 15 carbon atoms and acyl of an organiccarboxylic acid and aryl unsubstituted or substituted with at least onemember of the group consisting of halogen, —OH, alkoxy of 1 to 15 carbonatoms, alkenyloxy of 2 to 15 carbon atoms and acyl of an organiccarboxylic acid, R₂ is selected from the group consisting of hydrogen,alkyl of 1 to 15 carbon atoms, alkenyl of 2 to 15 carbon atoms andbenzyl unsubstituted or substituted with at least one member of thegroup consisting of halogen, —OH, alkoxy of 1 to 15 carbon atoms,alkenyloxy of 2 to 15 carbon atoms and acyl of an organic carboxylicacid, R₃ is selected from the group consisting of hydrogen, alkyl of 1to 15 carbon atoms, alkenyl of 2 to 15 carbon atoms, benzylunsubstituted or substituted with at least one member of the groupconsisting of halogen, —OH, alkoxy of 1 to 15 carbon atoms, alkenyloxyof 2 to 15 carbon atoms and acyl of an organic carboxylic acid,hydroxyl, alkoxy of 1 to 15 carbon atoms, alkenyloxy of 2 to 15 carbonatoms, benzyloxy unsubstituted or substituted with at least one memberof the group consisting of halogen, —OH, alkoxy of 1 to 15 carbon atoms,alkenyloxy of 2 to 15 carbon atoms and acyl of an organic carboxylicacid, R₄ is selected from the group consisting of hydrogen, alkyl of 1to 15 carbon atoms, alkenyl of 2 to 15 carbon atoms, benzylunsubstituted or substituted with at least one member of the groupconsisting of halogen, —OH, alkoxy of 1 to 15 carbon atoms, alkenyloxyof 2 to 15 carbon atoms and acyl of an organic carboxylic acid andhydroxyl, and R₅ and R₆ are individually selected from the groupconsisting of hydrogen, alkyl of 1 to 15 carbon atoms, alkenyl of 2 to15 carbon atoms and benzyl unsubstituted or substituted with at leastone member of the group consisting of halogen, —OH, alkoxy of 1 to 15carbon atoms, alkenyloxy of 2 to 15 carbon atoms and acyl of an organiccarboxylic acid and a salt thereof with a non-toxic, pharmaceuticallyacceptable base and a pharmaceutically acceptable carrier.
 16. Acomposition useful as a curative agent for diseases affectingbones-cartilages comprising a compound of the formula

wherein R₁ is selected from the group consisting of alkyl of 1 to 15carbon atoms, benzyl unsubstituted or substituted with at least onemember of the group consisting of halogen, —OH, alkoxy of 1 to 15 carbonatoms, alkenyloxy of 2 to 15 carbon atoms and acyl of an organiccarboxylic acid and aryl unsubstituted or substituted with at least onemember of the group consisting of halogen, —OH, alkoxy of 1 to 15 carbonatoms, alkenyloxy of 2 to 15 carbon atoms and acyl of an organiccarboxylic acid, R₂ is selected from the group consisting of hydrogen,alkyl of 1 to 15 carbon atoms, alkenyl of 2 to 15 carbon atoms andbenzyl unsubstituted or substituted with at least one member of thegroup consisting of halogen, —OH, alkoxy of 1 to 15 carbon atoms,alkenyloxy of 2 to 15 carbon atoms and acyl of an organic carboxylicacid, R₃ is selected from the group consisting of alkyl of 1 to 15carbon atoms, alkenyl of 2 to 15 carbon atoms and benzyl unsubstitutedor substituted with at least one member of the group consisting ofhalogen, —OH, alkoxy of 1 to 15 carbon atoms, alkenyloxy of 2 to 15carbon atoms and acyl of an organic carboxylic acid, and R₈ is selectedfrom the group consisting of hydroxyl, alkyl of 1 to 15 carbon atoms,alkenyl of 2 to 15 carbon atoms and benzyl unsubstituted or substitutedwith at least one member of the group consisting of halogen, —OH, alkoxyof 1 to 15 carbon atoms, alkenyloxy of 2 to 15 carbon atoms and acyl ofan organic carboxylic acid, providing that when R₂ and R₃ are each3-methyl-2-butenyl, R₁ is methyl and R₈ is hydroxyl and in which two orthree members of the class consisting of R₂, R₃, and R₈ are each3-methyl-2-butenyl and the remaining member is hydrogen or hydroxyl whenR₁ is not R₂-propyl, 2-methylpropyl or 1-methylpropyl and a salt of anon-toxic, pharmaceutically acceptable base and a pharmaceuticallyacceptable carrier.
 17. A method for treating diseases ofbones-cartilages in warm-blooded animals comprisi g administering towarm-blooded animals a compound of claim 1 in an amount effective totreat or prevent diseases of bones-cartilages.